Anti-respiratory syncytial virus antibodies, and methods of their generation and use

ABSTRACT

Anti-RSV antibodies with neutralizing potency against RSV subtype A and RSV subtype B are provided, as well as nucleic acid sequences encoding such antibodies, methods for their identification, isolation, generation, and methods for their preparation and use are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional Patent Application No. 62/411,510, filed Oct. 21, 2016, the entire contents of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 31, 2016, is named “2009186_0166_SL.TXT” and is 851,610 bytes in size.

FIELD OF THE INVENTION

The invention relates, inter alia, to anti-Respiratory Syncytial Virus (RSV) antibodies and functional fragments thereof, nucleic acid sequences encoding such antibodies and methods and reagents for their preparation and use.

BACKGROUND OF THE INVENTION

All references cited herein, including without limitation patents, patent applications, and non-patent references and publications referenced throughout are hereby expressly incorporated by reference in their entireties for all purposes.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly, is the leading cause of infant hospitalization in the United States and accounts for an estimated 64 million infections and 160,000 deaths world-wide each year. However, despite decades of research, the development of a safe and effective vaccines or therapeutic and/or prophylactic antibodies against RSV has remained elusive, highlighting the need for novel strategies that induce or provide protective immune responses. (1-3). Indeed, to date there are currently no approved RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab (marketed as Synagis®) is restricted to high-risk infants in part due to its modest efficacy.

Certain populations of children are at risk for developing an RSV infection and these include preterm infants (Hall et al., 1979, New Engl. J. Med. 300:393-396), children with congenital malformations of the airway, children with bronchopulmonary dysplasia (Groothuis et al., 1988, Pediatrics 82:199-203), children with congenital heart disease (MacDonald et al., New Engl. J. Med. 307:397-400), and children with congenital or acquired immunodeficiency (Ogra et al., 1988, Pediatr. Infect. Dis. J. 7:246-249; and Pohl et al., 1992, J. Infect. Dis. 165:166-169), and cystic fibrosis (Abman et al., 1988, J. Pediatr. 1 13:826-830).

RSV can infect the adult population as well. In this population, RSV causes primarily an upper respiratory tract disease, although elderly patients may be at greater risk for a serious infection and pneumonia (Evans, A. S., eds., 1989, Viral Infections of Humans. Epidemiology and Control, 3^(rd) ed., Plenum Medical Book, New York at pages 525-544), as well as adults who are immunosuppressed, particularly bone marrow transplant patients (Hertz et al., 1989, Medicine 68:269-281). Other at risk patients include those suffering from congestive heart failure and those suffering from chronic obstructive pulmonary disease (i.e. COPD). There have also been reports of epidemics among nursing home patients and institutionalized young adults (Falsey, A. R., 1991, Infect. Control Hosp. Epidemiol. 12:602-608; and Garvie et al., 1980, Br. Med. J. 281:1253-1254).

While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Similar to other pneumoviruses, RSV expresses two major surface glycoproteins: the fusion protein (F) and the attachment protein (G). Although both have been shown to induce protective neutralizing antibody responses, F is less genetically variable than G, is absolutely required for infection, and is the target for the majority of neutralizing activity in human serum (4-8). RSV F is also the target of the monoclonal antibody palivizumab, which is used to passively protect high-risk infants from severe disease (9). Consequently, the RSV F protein is considered to be a highly attractive target for vaccines and antibody-based therapies.

The mature RSV F glycoprotein initially exists in a metastable prefusion conformation (preF) (10), before undergoing a conformational change that leads to insertion of the hydrophobic fusion peptide into the host-cell membrane. Subsequent refolding of F into a stable, elongated postfusion conformation (postF) (11, 12) results in fusion of the viral and host-cell membranes. Due to its inherent instability, the preF protein has the propensity to prematurely trigger into postF, both in solution and on the viral surface (13). Recently, stabilization of preF has been achieved by protein engineering (14, 15), and stabilized preF has been shown to induce higher titers of neutralizing antibodies than postF in animal models (15).

Despite the importance of neutralizing antibodies in protection against severe RSV disease, our understanding of the human antibody response to RSV has been limited to studies of human sera and a small number of RSV-specific human monoclonal antibodies (16-19). The epitopes recognized by these human antibodies, as well as several murine antibodies, have defined at least four ‘antigenic sites’ on RSV F (1, 10, 16, 18-20) (see also, e.g., Table 1). Three of these sites—I, II, and IV—are present on both pre- and postF, whereas antigenic site ø exists exclusively on preF. Additional preF-specific epitopes have been defined by antibodies MPE8 (17) and AM14 (21). Although serum mapping studies have shown that site ø-directed antibodies are responsible for a large proportion of the neutralizing antibody response in most individuals (8), there are additional antibody specificities that contribute to serum neutralizing activity that remain to be defined. In addition, it was heretofore unknown whether certain antibody sequence features are required for recognition of certain neutralizing sites, as observed for other viral targets (22-25). Accordingly, understanding the relationship between neutralization potency and epitope specificity would be advantageous in the selection and/or design of vaccine antigens, as well as therapeutic and/or prophylactic antibodies, which induce potent neutralizing responses to RSV.

While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Ribavirin, which is the only drug approved for treatment of infection, has been shown to be effective in the treatment of pneumonia and bronchiolitis associated with RSV infection, and has been shown to modify the course of severe RSV disease in immunocompetent children (Smith et al., 1991, New Engl. J. Med. 325:24-29). The use of ribavirin is limited due to concerns surrounding its potential risk to pregnant women who may be exposed to the aerosolized drug while it is being administered in a hospital environment.

Similarly, while a vaccine may be useful, no commercially available vaccine has been developed to date. Several vaccine candidates have been abandoned and others are under development (Murphy et al., 1994, Virus Res. 32: 13-36). The development of a vaccine has proven to be problematic. In particular, immunization would be required in the immediate neonatal period since the peak incidence of lower respiratory tract disease occurs at 2-5 months of age. However, it is known that the neonatal immune response is immature at that time. Plus, the infant at that point in time still has high titers of maternally acquired RSV antibody, which might reduce vaccine immunogenicity (Murphy et al., 1988, J. Virol. 62:3907-3910; and Murphy et al, 1991, Vaccine 9:185-189).

Currently, the only approved approach to prophylaxis of RSV disease is passive immunization. For example, the humanized antibody, palivizumab (SYNAGIS®), which is specific for an epitope on the F protein, is approved for intramuscular administration to pediatric patients for prevention of serious lower respiratory tract disease caused by RSV at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is a composite of human (95%) and murine (5%) antibody sequences. (Johnson et al, (1997), J. Infect. Diseases 176:1215-1224 and U.S. Pat. No. 5,824,307).

Although SYNAGIS® has been successfully used for the prevention of RSV infection in pediatric patients, multiple intramuscular doses of 15 mg/kg of SYNAGIS® are required to achieve a prophylactic effect. The necessity for the administration of multiple intramuscular doses of antibody requires repeated visits to the doctor's office, which is not only inconvenient for the patient but can also result in missed doses.

Efforts were made to improve on the therapeutic profile of an anti-RSV-F antibody, and this lead to the identification and development of motavizumab, also referred to as NUMAX™. However, clinical testing revealed that certain of the patients being administered motavizumab were having severe hypersensitivity reactions. Further development of this humanized anti-RSV-F antibody was then discontinued.

Other antibodies to RSV-F protein have been described and can be found in U.S. Pat. Nos. 6,656,467; 5,824,307, 7,786,273; 7,670,600; 7,083,784; 6,818,216; 7,700,735; 7,553,489; 7,323,172; 7,229,619; 7,425,618; 7,740,851; 7,658,921; 7,704,505; 7,635,568; 6,855,493; 6,565,849; 7,582,297; 7,208,162; 7,700,720; 6,413,771; 5,811,524; 6,537,809; 5,762,905; 7,070,786; 7,364,742; 7,879,329; 7,488,477; 7,867,497; 5,534,411; 6,835,372; 7,482,024; 7,691,603; 8,562,996; 8,568,726; 9,447,173; US20100015596; WO2009088159A1; and WO2014159822. To date, none other than SYNAGIS® has been approved by a regulatory agency for use in preventing an RSV infection.

There remains a need for the provision of highly specific, high affinity, and highly potent neutralizing anti-RSV antibodies and antigen-binding fragments thereof with neutralize at least one, but preferably both, of subtype A and subtype B RSV viral strains, and which preferentially recognize PreF relative to PostF conformations of the F protein. There also remains a need for the provision of anti-RSV and anti-HMPV cross-neutralizing antibodies and antigen-binding fragments thereof.

SUMMARY OF THE INVENTION

Applicant has now discovered, isolated, and characterized, inter alia, an extensive panel of RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult human donor and used these antibodies to comprehensively map the antigenic topology of RSV F. A large proportion of the RSV F-specific human antibody repertoire was advantageously comprised of antibodies with greatly enhanced specificity for the PreF conformation of the F protein (relative to the PostF form), many if not most of which exhibited remarkable potency in neutralization assays against one or both of RSV subtype A and RSV subtype B strains. Indeed, a large number of these antibodies display neutralization potencies that are multiple-fold greater—some 5- to 100-fold greater or more—to previous anti-RSV therapeutic antibodies, such as D25 and pavlizumamab thus serve as attractive therapeutic and/or prophylactic candidates for treating and/or preventing RSV infection and disease.

The most potent antibodies were found to target two distinct antigenic sites that are located near the apex of the preF trimer, providing strong support for the development of therapeutic and/or prophylactic antibodies targeting these antigenic sites, as well as preF-based vaccine candidates that preserve these antigenic sites. Furthermore, the neutralizing antibodies described and disclosed herein represent new opportunities for the prevention of severe RSV disease using passive immunoprophylaxis.

Given the role that the F protein plays in fusion of the virus with the cell and in cell to cell transmission of the virus, the antibodies described herein provide a method of inhibiting that process and as such, may be used for preventing infection of a patient exposed to, or at risk for acquiring an infection with RSV, or for treating and/or ameliorating one or more symptoms associated with RSV infection in a patient exposed to, or at risk for acquiring an infection with RSV, or suffering from infection with RSV. The antibodies and pharmaceutical compositions described herein may also be used to prevent or to treat an RSV infection in a patient who may experience a more severe form of the RSV infection due to an underlying or pre-existing medical condition. A patient who may benefit from treatment with an antibody and/or a pharmaceutical composition of the invention may be a pre-term infant, a full-term infant born during RSV season (approximately late fall (November) through early spring (April)) that is at risk because of other pre-existing or underlying medical conditions including congenital heart disease or chronic lung disease, a child greater than one year of age with or without an underlying medical condition, an institutionalized or hospitalized patient, or an elderly adult (>65 years of age) with or without an underlying medical condition, such as congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD). A patient who may benefit from such therapy may suffer from a medical condition resulting from a compromised pulmonary, cardiovascular, neuromuscular, or immune system. For example, the patient may suffer from an abnormality of the airway, or an airway malfunction, a chronic lung disease, a chronic or congenital heart disease, a neuromuscular disease that compromises the handling of respiratory secretions, or the patient may be immunosuppressed due to severe combined immunodeficiency disease or severe acquired immunodeficiency disease, or from any other underlying infectious disease or cancerous condition that results in immunosuppression, or the patient may be immunosuppressed due to treatment with an immunosuppressive drug (e.g., any drug used for treating a transplant patient) or radiation therapy. A patient who may benefit from the antibodies and/or pharmaceutical compositions of the invention may be a patient that suffers from chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), bronchopulmonary dysplasia, congestive heart failure (CHF), or congenital heart disease.

Because the inventive antibodies and antigen-binding fragments thereof are more effective at neutralization of RSV compared to known antibodies, lower doses of the antibodies or antibody fragments or pharmaceutical compositions of the invention could be used to achieve a greater level of protection against infection with RSV, and more effective treatment and/or amelioration of symptoms associated with an RSV infection. Accordingly, the use of lower doses of antibodies, or fragments thereof, which immunospecifically bind to RSV-F antigen and/or pharmaceutical compositions may result in fewer or less severe adverse events. Likewise, the use of more effective neutralizing antibodies may result in a diminished need for frequent administration of the antibodies or antibody fragments or pharmaceutical compositions than previously envisioned as necessary for the prevention of infection, or for virus neutralization, or for treatment or amelioration of one or more symptoms associated with an RSV infection. Symptoms of RSV infection may include a bluish skin color due to lack of oxygen (hypoxia), breathing difficulty (rapid breathing or shortness of breath), cough, croupy cough (“seal bark” cough), fever, nasal flaring, nasal congestion (stuffy nose), apnea, decreased appetite, dehydration, poor feeding, altered mental status, or wheezing.

Such antibodies or pharmaceutical compositions may be useful when administered prophylactically (prior to exposure to the virus and infection with the virus) to lessen the severity, or duration of a primary infection with RSV, or ameliorate at least one symptom associated with the infection. The antibodies or pharmaceutical compositions may be used alone or in conjunction with a second agent useful for treating an RSV infection. In certain embodiments, the antibodies or pharmaceutical compositions may be given therapeutically (after exposure to and infection with the virus) either alone, or in conjunction with a second agent to lessen the severity or duration of the primary infection, or to ameliorate at least one symptom associated with the infection. In certain embodiments, the antibodies or pharmaceutical compositions may be used prophylactically as stand-alone therapy to protect patients who are at risk for acquiring an infection with RSV, such as those described above. Any of these patient populations may benefit from treatment with the antibodies or pharmaceutical compositions of the invention, when given alone or in conjunction with a second agent, including for example, an anti-viral therapy, such as ribavirin, or other anti-viral vaccines.

The antibodies of the invention can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab′)₂ or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., (2000), J. Immunol. 164:1925-1933).

Accordingly, in certain embodiments are provided isolated antibodies or antigen-binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one, at least two, at least three, at least four, at least five, or at least six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence such antibodies or the antigen-binding fragments thereof are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; at least 100% and/or all percentages of identity in between; to at least one, at least two, at least three, at least four, at least five, or at least six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics: a) the antibodies or antigen-binding fragments thereof cross-compete with said antibodies or antigen-binding fragments thereof for binding to RSV-F; b) the antibodies or antigen-binding fragments thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form; c) the antibodies or antigen-binding fragments thereof display a clean or low polyreactivity profile; d) the antibodies or antigen-binding fragments thereof display neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F at Site ø, Site I, Site II, Site III, Site IV, or Site V; f) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F Site ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the antibodies or antigen-binding fragments thereof interact comprises the α3 helix and β3/β4 hairpin of PreF; h) the antibodies or antigen-binding fragments thereof display an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 μg/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml; i) the binding affinities and/or epitopic specificities of the antibodies or antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinities and/or epitopic specificities of said antibodies or antigen-binding fragments thereof for the RSV-F or RSV-F DS-Cav1; j) the antibodies or antigen-binding fragments thereof display a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV); k) the antibodies or antigen-binding fragments thereof do not complete with D25, MPE8, palivizumab, or motavizumab; or 1) the antibodies or antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC₅₀) than D25 and/or palivizumab.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1) above.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In other embodiments are provided isolated nucleic acid sequences encoding antibodies, light and/or heavy chains thereof, antigen-binding fragments thereof, or light and/or heavy chains encoding such antigen-binding fragments according to any of the other embodiments disclosed herein.

In other embodiments are provided expression vectors comprising isolated nucleic acid sequences according to other embodiments disclosed herein.

In other embodiments are provided host cells transfected, transformed, or transduced with nucleic acid sequences or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided pharmaceutical compositions comprising one or more of the isolated antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided pharmaceutical compositions comprising a nucleic acid sequence of the invention, e.g., one or more nucleic acid sequences encoding at least one of a light or heavy chain of an antibody or both according other embodiments disclosed herein; or one or more the expression vectors according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided transgenic organisms comprising nucleic acid sequences according to other embodiments disclosed herein; or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need there of or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) nucleic acid sequences according to other embodiments disclosed herein; an expression vector according to other embodiments disclosed herein; a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) a nucleic acid sequences according to other embodiments disclosed herein; c) an expression vector according to other embodiments disclosed herein; d) a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In other embodiments are provided methods according to other embodiments wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 4, 11, and 62 as disclosed in Table 6.

In other embodiments are provided methods according to other embodiments wherein the method further comprises administering to the patient a second therapeutic agent.

In other embodiments are provided methods according to other embodiments, wherein the second therapeutic agent is selected group consisting of an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

In certain embodiments are provided pharmaceutical compositions comprising any one or more of the isolated antibodies or antigen-binding fragments thereof, or one or more nucleic acid sequences encoding at least one of a light chain or heavy chain of an antibody according to other embodiments disclosed herein or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier and/or excipient.

In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1F illustrate the anti-RSV repertoire cloning and sequence analysis of the identified and isolated antibodies. FIG. 1A: RSV F-specific B cell sorting. FACS plots show RSV F reactivity of IgG⁺ and IgA⁺ B cells from the healthy adult donor. B cells in quadrant 2 (Q2) were single cell sorted. FIG. 1B: Isotype analysis. Index sort plots show the percentage of RSV F-specific B cells that express IgG or IgA. FIG. 1C: Clonal lineage analysis. Each slice represents one clonal lineage; the size of the slice is proportional to the number of clones in the lineage. The total number of clones is shown in the center of the pie. Clonal lineages were assigned based on the following criteria: 1) matching of variable and joining gene segments; 2) identical CDR3 loop lengths; and 3) >80% homology in CDR3 nucleotide sequences. FIG. 1D: VH repertoire analysis. VH germline genes were considered to be enriched in the RSV repertoire if a given gene was found to be enriched by greater than 3-fold over non-RSV-specific repertoires (33). FIG. 1E: CDRH3 length distribution. FIG. 1F: Somatic hypermutation in VH (excluding CDRH3). Red bar indicates the average number of nucleotide substitutions. Each clonal lineage is only represented once in FIG. 1D and FIG. 1E. Data for non-RSV reactive IgGs were derived from published sequences obtained by high-throughput sequencing of re-arranged antibody variable gene repertoires from healthy individuals (33).

FIGS. 2A-2D illustrate the similar antibody preferences observed for conformational state and subtype of RSV F in the repertoire. FIG. 2A: IgG affinities for preF and postF are plotted as shown. FIG. 2B: Percentage of antibodies within the donor repertoire that recognized both conformations of F (green) or bind only to preF (blue) or postF (orange). FIG. 2C: Percentage of antibodies within the donor repertoire that bind specifically to subtype A (green), subtype B (blue), or both subtypes A and B (red). N.B., non-binder. IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. FIG. 2D: Polyreactivity analysis of anti-RSV antibodies. The polyreactivity of the isolated anti-RSV F antibodies was measured using a previously described assay (42, 43). Three panels of control antibodies were included for comparison: a group of 138 antibodies currently in clinical trials, 39 antibodies that have been approved for clinical use and 14 broadly neutralizing HIV antibodies.

FIGS. 3A-3G illustrate mapping and specificities of anti-RSV antibodies for antigenic sites spanning the surface of PreF and PostF. FIG. 3A: The previously determined structure of preF with one protomer shown as ribbons and with six antigenic sites rainbow colored from red to purple. FIG. 3B: The percentage of antibodies targeting each antigenic site is shown. FIG. 3C: Percentage of preF-specific antibodies targeting each antigenic site. FIG. 3D: Apparent antibody binding affinities for subtype A PreF antigenic sites. FIG. 3E: Apparent binding affinities for subtype A postF antigenic sites. FIG. 3F: Apparent antibody binding affinities for subtype B PreF antigenic sites. FIG. 3G. Apparent binding affinities for subtype B postF. Only antibodies with apparent binding affinities greater than 2 nM were included in this analysis, since antibodies with lower affinity could not be reliably mapped. Red bars show the median and the dotted grey line is at 2 nM. N.B., non-binder.

FIGS. 4A-4G illustrate neutralizing potencies of anti-RSV antibodies and correlation between potency and Pref vs. PostF specificity for each of RSV subtypes A and B. FIG. 4A: Neutralization IC₅₀s for the antibodies isolated from the donor repertoire. Data points are colored based on neutralization potency, according to the legend on the right. Red and blue dotted lines depict motavizumab and D25 IC₅₀s, respectively. FIG. 4B: Percentage of neutralizing antibodies in the donor repertoire against RSV subtype A or subtype B, stratified by potency as indicated in the legend in the right portion of the figure. FIG. 4C: Percentage of antibodies within the donor repertoire that neutralized both RSV subtypes A and B (red) or neutralized only RSV subtype A (green) or subtype B (blue). FIG. 4D: Apparent binding affinities for subtype A, preF and postF, plotted for each antibody (IgG K_(D)s were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B.) FIG. 4E: Neutralization IC₅₀s plotted for RSV subtype A preF-specific, postF-specific, and cross-reactive antibodies. (Red and blue dotted lines depict motavizumab and D25 IC₅₀s, respectively. Red bars depict median. N.B., non-binder; N.N., non-neutralizing). FIG. 4F: Apparent antibody binding affinities for subtype B, preF and postF. FIG. 4G: IC₅₀s plotted for RSV subtype B preF-specific, postF-specific and cross-reactive antibodies. (Black bar depicts median. N.B., non-binder; N.N., non-neutralizing.)

FIGS. 5A-5C illustrate that the most potent neutralizing antibodies bind with high affinity to preF and recognize antigenic sites ø and V. FIG. 5A: apparent preF K_(D) plotted against neutralization IC₅₀ and colored according to antigenic site, as shown in the legend at right of FIG. 5C. FIG. 5B: apparent postF K_(D) plotted against neutralization IC₅₀ and colored as in FIG. 5A. FIG. 5C: antibodies grouped according to neutralization potency and colored by antigenic site as in legend at right. N.B., non-binder; N.N., non-neutralizing. IgG K_(D)s were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. Statistical significance was determined using an unpaired two-tailed t test. The Pearson's correlation coefficient, r, was calculated using Prism software version 7.0. Antibodies that failed to bind or neutralize were excluded from the statistical analysis due to the inability to accurately calculate midpoint concentrations.

FIGS. 6A-6C illustrate the nature and purification of pre- and postF sorting probes. FIG. 6A: Schematic of fluorescent prefusion RSV F probe shows one PE-conjugated streptavidin molecule bound by four avi-tagged trimeric prefusion F molecules. FIG. 6B: Coomassie-stained SDS-PAGE gel demonstrating the isolation of RSV F with a single AviTag per trimer using sequential Ni-NTA and Strep-Tactin purifications, as described in the Methods. FIG. 6C: Fluorescence size-exclusion chromatography (FSEC) trace of the tetrameric probes on a Superose 6 column. Positions of molecular weight standards are indicated with arrows.

FIGS. 7A-7C illustrate the generation and validation of preF patch panel mutants. FIG. 7A: Panel of RSV F variants used for epitope mapping. FIG. 7B: Prefusion RSV F shown as molecular surface with one protomer colored in white. The nine variants, each containing a patch of mutations, are uniquely colored according to the table in FIG. 7A. FIG. 7C: Binding of each IgG to fluorescently labeled beads coupled to each of the variants listed in FIG. 7A was measured using PE-conjugated anti-human Fc antibody on a FLEXMAP 3D flow cytometer (Luminex). Reduced binding of D25 and motavizumab to patches 1 and 5, respectively, is consistent with their structurally defined epitopes (10, 11). AM14 binding was reduced for both patch 3 and patch 9, due to its unique protomer-spanning epitope (21). This characteristic binding profile was used to assist in the classification of other possible quaternary-specific antibodies in the panel.

FIG. 8 illustrates the antigenic site V resides between the epitopes recognized by D25, MPE8 and motavizumab. Prefusion F is shown with one promoter as a cartoon colored according to antigenic site location and the other two protomers colored grey. D25 and motavizumab Fabs are shown in blue and pink, respectively. The MPE8 binding site is circled in black. Antigenic site V is located between the binding sites of D25 and MPE8 within one protomer, explaining the competition between site-V directed antibodies and these controls. Competition with motavizumab may occur across two adjacent protomers (left) or within one protomer (right), depending on the angle-of-approach of these site-V directed antibodies.

FIG. 9 illustrates percentage of anti-RSV antibodies demonstrating the indicated neutralizing activities of preF-specific, postF-specific, and cross-reactive antibodies. Antibodies were stratified according to neutralization potency and the percentage of antibodies in each group that were preF-specific (pink), postF-specific (white) or cross-reactive (orange) were plotted for subtype A (left panel) and subtype B (right panel).

FIGS. 10A-10C illustrate the relationship between subtype B neutralization and antigenic site specificity for anti-RSV antibodies. FIG. 10A: Subtype B preF affinity plotted against neutralization IC₅₀ for all antibodies and colored by antigenic site according to the color scheme depicted in FIG. 10C, right portion. FIG. 10B: PostF affinity plotted against IC₅₀ and colored as in FIG. 10A. FIG. 10C: Antibodies with preF affinities higher than 2 nM grouped according to neutralization potency and colored by antigenic site (right portion).

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

Definitions

“Respiratory Syncytial Virus-F protein”, also referred to as “RSV-F” or “RSV F” is a type I transmembrane surface protein, which has an N terminal cleaved signal peptide and a membrane anchor near the C terminus (Collins, P. L. et al., (1984), PNAS (USA) 81:7683-7687). The RSV-F protein is synthesized as an inactive 67 KDa precursor denoted as F0 (Calder, L. J.; et al., Virology (2000), 277, 122-131. The F0 protein is activated proteolytically in the Golgi complex by a furin-like protease at two sites, yielding two disulfide linked polypeptides, F2 and F1, from the N and C terminal, respectively. There is a 27 amino acid peptide released called “pep27”. There are furin cleavage sites (FCS) on either side of the pep27 (Collins, P. L.; Mottet, G. (1991), J. Gen. Virol., 72: 3095-3101; Sugrue, R. J, et al. (2001), J. Gen. Virol., 82, 1375-1386). The F2 subunit consists of the Heptad repeat C (HRC), while the F1 contains the fusion polypeptide (FP), heptad repeat A (HRA), domain I, domain II, heptad repeat B (HRB), transmembrane (TM) and cytoplasmic domain (CP) (See Sun, Z. et al. Viruses (2013), 5:21 1-225). The RSV-F protein plays a role in fusion of the virus particle to the cell membrane, and is expressed on the surface of infected cells, thus playing a role in cell to cell transmission of the virus and syncytia formation. The amino acid sequence of the RSV-F protein is provided in GenBank as accession number AAX23994.

A stabilized variant of the PreF trimeric conformation of RSV-F, termed “RSV-DS-Cav1”, or “DS-Cav1” disclosed in, inter alia, Stewart-Jones et al., PLos One, Vol. 10(6)):e0128779 and WO 2011/050168, was used in the identification, isolation, and characterization of the antibodies disclosed herein.

The term “laboratory strain” as used herein refers to a strain of RSV (subtype A or B) that has been passaged extensively in in vitro cell culture. A “laboratory strain” can acquire adaptive mutations that may affect their biological properties. A “clinical strain” as used herein refers to an RSV isolate (subtype A or B), which is obtained from an infected individual and which has been isolated and grown in tissue culture at low passage.

The term “effective dose 99” or “ED₉₉” refers to the dosage of an agent that produces a desired effect of 99% reduction of viral forming plaques relative to the isotype (negative) control. In the present invention, the ED₉₉ refers to the dosage of the anti-RSV-F antibodies that will neutralize the virus infection (e.g., reduce 99% of viral load) in vivo, as described in Example 5.

The term “IC₅₀” refers to the “half maximal inhibitory concentration”, which value measures the effectiveness of compound (e.g., anti-RSV-F antibody) inhibition towards a biological or biochemical utility. This quantitative measure indicates the quantity required for a particular inhibitor to inhibit a given biological process by half. In certain embodiments, RSV virus neutralization potencies for anti-RSV and/or anti-RSV/anti-HMPV cross-neutralizing antibodies disclosed herein are expressed as neutralization IC₅₀ values.

“Palivizumab”, also referred to as “SYNAGIS®”, is a humanized anti-RSV-F antibody with heavy and light chain variable domains having the amino acid sequences as set forth in U.S. Pat. Nos. 7,635,568 and 5,824,307. This antibody, which immunospecifically binds to the RSV-F protein, is currently FDA-approved for the passive immunoprophylaxis of serious RSV disease in high-risk children and is administered intramuscularly at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is composed of 95% human and 5% murine antibody sequences. See also Johnson et al., (1997), J. Infect. Diseases 176:1215-1224.

“Motavizumab”, also referred to as “NUMAX™”, is an enhanced potency RSV-F-specific humanized monoclonal antibody derived by in vitro affinity maturation of the complementarity-determining regions of the heavy and light chains of palivizumab. For reference purposes, the amino acid sequence of the NUMAX™ antibody is disclosed in U.S. Patent Publication 2003/0091584 and in U.S. Pat. No. 6,818,216 and in Wu et al., (2005) J. Mol. Bio. 350(1):126-144 and in Wu et al. (2007) J. Mol. Biol. 368:652-665. It is also shown herein as SEQ ID NO: 359 for the heavy chain and as SEQ ID NO: 360 for the light chain of the antibody.

As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of an upper and/or lower respiratory tract RSV infection and/or human metapneumovirus (HMPV), otitis media, or a symptom or respiratory condition related thereto (such as asthma, wheezing, or a combination thereof) resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents). In certain embodiments, such terms refer to the reduction or inhibition of the replication of RSV and/or HMPV, the inhibition or reduction in the spread of RSV and/or HMPV to other tissues or subjects (e.g., the spread to the lower respiratory tract), the inhibition or reduction of infection of a cell with a RSV and/or HMPV, or the amelioration of one or more symptoms associated with an upper and/or lower respiratory tract RSV infection or otitis media.

As used herein, the terms “prevent,” “preventing,” and “prevention” refer to the prevention or inhibition of the development or onset of an upper and/or lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto in a subject, the prevention or inhibition of the progression of an upper respiratory tract RSV and/or HMPV infection to a lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent), the prevention of a symptom of an upper and/or lower tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto, or the administration of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents). As used herein, the terms “ameliorate” and “alleviate” refer to a reduction or diminishment in the severity a condition or any symptoms thereof.

The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds (i.e., “full antibody molecules”), as well as multimers thereof (e.g. IgM) or antigen-binding fragments thereof. Each heavy chain (HC) is comprised of a heavy chain variable region (“HCVR” or “V_(H)”) and a heavy chain constant region (comprised of domains C_(H)1, C_(H)2 and C_(H)3). Each light chain (LC) is comprised of a light chain variable region (“LCVR or “V_(L)”) and a light chain constant region (C_(L)). The V_(H) and V_(L) regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each V_(H) and V_(L) is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, the FRs of the antibody (or antigen-binding fragment thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. Accordingly, the CDRs in a heavy chain are designated “CHRH1”, “CDRH2”, and “CDRH3”, respectively, and the CDRs in a light chain are designated “CDRL1”, “CDRL2”, and “CDRL3”.

Substitution of one or more CDR residues or omission of one or more CDRs is also possible. Antibodies have been described in the scientific literature in which one or two CDRs can be dispensed with for binding. Padlan et al. (1995 FASEB J. 9:133-139) analyzed the contact regions between antibodies and their antigens, based on published crystal structures, and concluded that only about one fifth to one third of CDR residues actually contact the antigen. Padlan also found many antibodies in which one or two CDRs had no amino acids in contact with an antigen (see also, Vaj dos et al. 2002 J Mol Biol 320:415-428).

CDR residues not contacting antigen can be identified based on previous studies (for example residues H60-H65 in CDRH2 are often not required), from regions of Kabat CDRs lying outside Chothia CDRs, by molecular modeling and/or empirically. If a CDR or residue(s) thereof is omitted, it is usually substituted with an amino acid occupying the corresponding position in another human antibody sequence or a consensus of such sequences. Positions for substitution within CDRs and amino acids to substitute can also be selected empirically.

The fully human monoclonal antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the V_(H) and/or V_(L) domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

The present invention also includes fully monoclonal antibodies comprising variants of any of the CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes antibodies having CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the CDR amino acid sequences disclosed herein.

The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human mAbs of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.

However, the term “human antibody”, as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse), have been grafted onto human FR sequences.

The term “humanized antibody” refers to human antibody in which one or more CDRs of such antibody have been replaced with one or more corresponding CDRs obtained a non-human derived (e.g., mouse, rat, rabbit, primate) antibody. Humanized antibodies may also include certain non-CDR sequences or residues derived from such non-human antibodies as well as the one or more non-human CDR sequence. Such antibodies may also be referred to as “chimeric antibodies”.

The term “recombinant” generally refers to any protein, polypeptide, or cell expressing a gene of interest that is produced by genetic engineering methods. The term “recombinant” as used with respect to a protein or polypeptide, means a polypeptide produced by expression of a recombinant polynucleotide. The proteins used in the immunogenic compositions of the invention may be isolated from a natural source or produced by genetic engineering methods.

The antibodies of the invention may, in some embodiments, be recombinant human antibodies. The term “recombinant human antibody”, as used herein, is intended to include all antibodies, including human or humanized antibodies, that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V_(H) and V_(L) regions of the recombinant antibodies are sequences that, while derived from and related to human germline V_(H) and V_(L) sequences, may not naturally exist within the human antibody germline repertoire in vivo.

The term “specifically binds,” or “binds specifically to”, or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about 1×10⁻⁶ M or less (e.g., a smaller K_(D) denotes a tighter binding). Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. As described herein, antibodies have been identified by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), which bind specifically to RSV-F. Moreover, multi-specific antibodies that bind to RSV-F protein and one or more additional antigens, such as an antigen expressed by HMPV, or a bi-specific that binds to two different regions of RSV-F are nonetheless considered antibodies that “specifically bind”, as used herein. In certain embodiments, the antibodies disclosed herein display equilibrium dissociation constants (and hence specificities) of about 1×10⁻⁶ M; about 1×10⁻⁷M; about 1×10⁻⁸ M; about 1×10⁻⁹ M; about 1×10⁻¹⁰ M; between about 1×10⁻⁶ M and about 1×10⁻⁷ M; between about 1×10⁻⁷ M and about 1×10⁻⁸ M; between about 1×10⁻⁸ M and about 1×10⁻⁹ M; or between about 1×10⁻⁹ M and about 1×10⁻¹⁰ M.

The term “high affinity” antibody refers to those mAbs having a binding affinity to RSV-F and/or HMPV, expressed as K_(D), of at least 10⁻⁹ M; more preferably 10⁻¹⁰ M, more preferably 10⁻¹¹ M, more preferably 10⁻¹² M as measured by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), or solution-affinity ELISA.

By the term “slow off rate”, “Koff” or “kd” is meant an antibody that dissociates from RSV-F, with a rate constant of 1×10⁻³ s⁻¹ or less, preferably 1×10⁻⁴ s⁻¹ or less, as determined by surface plasmon resonance, e.g., BIACORE™ or a ForteBio Octet HTX instrument (Pall Life Sciences).

The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. In certain embodiments, the terms “antigen-binding portion” of an antibody, or “antibody fragment”, as used herein, refers to one or more fragments of an antibody that retains the ability to bind to RSV-F and/or HMPV.

An antibody fragment may include a Fab fragment, a F(ab′)₂ fragment, a Fv fragment, a dAb fragment, a fragment containing a CDR, or an isolated CDR. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and (optionally) constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab′)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.

An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR, which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a V_(H) domain associated with a V_(L) domain, the V_(H) and V_(L) domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain V_(H)-V_(H), V_(H)-V_(L) or V_(L)-V_(L) dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric V_(H) or V_(L) domain.

In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) V_(H)-C_(H)1; (ii) V_(H)-C_(H)2; V_(H)—C_(H)3; (iv) V_(H)-C_(h)2; (v) V_(H)-C_(h)1-C_(h)2-C_(h)3; (vi) V_(H)-C_(H)2-C_(H)3; (vii) V_(H)-C_(L); V_(L)-C_(H)1; (ix) V_(L)-C_(H)2; (x) V_(L)-C_(H)3; (xi) V_(L)-C_(H)1-C_(H)2; (xii) V_(L)-C_(H)1-C_(H)2-C_(H)3; (xiii) V_(L)-C_(H)2-C_(H)3; and (xiv) V_(L)-C_(L). In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V_(H) or V_(L) domain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may be mono-specific or multi-specific (e.g., bi-specific). A multi-specific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multi-specific antibody format, including the exemplary bi-specific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.

The specific embodiments, antibody or antibody fragments of the invention may be conjugated to a therapeutic moiety (“immunoconjugate”), such as an antibiotic, a second anti-RSV-F antibody, an anti-HMPV antibody, a vaccine, or a toxoid, or any other therapeutic moiety useful for treating an RSV infection and/or an HMPV infection.

An “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies (Abs) having different antigenic specificities (e.g., an isolated antibody that specifically binds RSV-F and/or HMPV, or a fragment thereof, is substantially free of Abs that specifically bind antigens other than RSV-F and/or HMPV.

A “blocking antibody” or a “neutralizing antibody”, as used herein (or an “antibody that neutralizes RSV-F and/or HMPV activity”), is intended to refer to an antibody whose binding to RSV-F or to an HMPV antigen, as the case may be as disclosed herein, results in inhibition of at least one biological activity of RSV-F and/or HMPV. For example, an antibody of the invention may aid in blocking the fusion of RSV and/or HMPV to a host cell, or prevent syncytia formation, or prevent the primary disease caused by RSV and/or HMPV. Alternatively, an antibody of the invention may demonstrate the ability to ameliorate at least one symptom of the RSV infection and or HMPV infection. This inhibition of the biological activity of RSV-F and/or HMPV can be assessed by measuring one or more indicators of RSV-F and/or HMPV biological activity by one or more of several standard in vitro assays (such as a neutralization assay, as described herein) or in vivo assays known in the art (for example, animal models to look at protection from challenge with RSV and/or HMPV following administration of one or more of the antibodies described herein).

The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time biomolecular interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE™ system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).

The term “K_(D)”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. The term “epitope” also refers to a site on an antigen to which B and/or T cells respond. It also refers to a region of an antigen that is bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics.

The term “substantial identity”, or “substantially identical,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or GAP, as discussed below. Accordingly, nucleic acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

In certain embodiments, the disclosed antibody nucleic acid sequences are, e.g, at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

In other embodiments, the disclosed antibody nucleic acid sequences are, e.g, at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

As applied to polypeptides, the term “substantial identity” or “substantially identical” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 90% sequence identity, even more preferably at least 95%, 98% or 99% sequence identity. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another.

In certain embodiments, the disclosed antibody amino acid sequences are, e.g, at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

In other embodiments, the disclosed antibody amino acid sequences are, e.g, at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

Preferably, residue positions, which are not identical, differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. (See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331). Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate, and 7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA with default or recommended parameters; a program in GCG Version 6.1. FASTA {e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. (See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and (1997) Nucleic Acids Res. 25:3389 402).

In certain embodiments, the antibody or antibody fragment for use in the method of the invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first and second Ig C_(H)3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig C_(H)3 domain binds Protein A and the second Ig C_(H)3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second C_(H)3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second C_(H)3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 mAbs; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 mAbs; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 mAbs. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.

By the phrase “therapeutically effective amount” is meant an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

An “immunogenic composition” relates to a composition containing an antigen/immunogen, e.g., a microorganism, such as a virus or a bacterium, or a component thereof, a protein, a polypeptide, a fragment of a protein or polypeptide, a whole cell inactivated, subunit or attenuated virus, or a polysaccharide, or combination thereof, administered to stimulate the recipient's humoral and/or cellular immune systems to one or more of the antigens/immunogens present in the immunogenic composition. The immunogenic compositions of the present invention can be used to treat a human susceptible to RSV and/or HMPV infection or suspected of having or being susceptible to RSV and/or HMPV infection, by means of administering the immunogenic compositions via a systemic route. These administrations can include injection via the intramuscular (i.m.), intradermal (i.d.), intranasal or inhalation route, or subcutaneous (s.c.) routes; application by a patch or other transdermal delivery device. In one embodiment, the immunogenic composition may be used in the manufacture of a vaccine or in the elicitation of polyclonal or monoclonal antibodies that could be used to passively protect or treat a mammal.

The terms “vaccine” or “vaccine composition”, which are used interchangeably, refer to a composition comprising at least one immunogenic composition that induces an immune response in an animal.

In certain embodiments, a protein of interest comprises an antigen. The terms “antigen,” “immunogen,” “antigenic,” “immunogenic,” “antigenically active,” and “immunologically active” when made in reference to a molecule, refer to any substance that is capable of inducing a specific humoral and/or cell-mediated immune response. In one embodiment, the antigen comprises an epitope, as defined above.

“Immunologically protective amount”, as used herein, is an amount of an antigen effective to induce an immunogenic response in the recipient that is adequate to prevent or ameliorate signs or symptoms of disease, including adverse health effects or complications thereof. Either humoral immunity or cell-mediated immunity or both can be induced. The immunogenic response of an animal to a composition can be evaluated, e.g., indirectly through measurement of antibody titers, lymphocyte proliferation assays, or directly through monitoring signs and symptoms after challenge with the microorganism. The protective immunity conferred by an immunogenic composition or vaccine can be evaluated by measuring, e.g., reduction of shed of challenge organisms, reduction in clinical signs such as mortality, morbidity, temperature, and overall physical condition, health and performance of the subject. The immune response can comprise, without limitation, induction of cellular and/or humoral immunity. The amount of a composition or vaccine that is therapeutically effective can vary, depending on the particular organism used, or the condition of the animal being treated or vaccinated.

An “immune response”, or “immunological response” as used herein, in a subject refers to the development of a humoral immune response, a cellular-immune response, or a humoral and a cellular immune response to an antigen/immunogen. A “humoral immune response” refers to one that is at least in part mediated by antibodies. A “cellular immune response” is one mediated by T-lymphocytes or other white blood cells or both, and includes the production of cytokines, chemokines and similar molecules produced by activated T-cells, white blood cells, or both. Immune responses can be determined using standard immunoassays and neutralization assays, which are known in the art.

“Immunogenicity”, as used herein, refers to the capability of a protein or polypeptide to elicit an immune response directed specifically against a bacteria or virus that causes the identified disease.

Unless specifically indicated otherwise, the term “antibody,” as used herein, shall be understood to encompass antibody molecules comprising two immunoglobulin heavy chains and two immunoglobulin light chains (i.e., “full antibody molecules”) as well as antigen-binding fragments thereof. The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.

Preparation of Human Antibodies

As disclosed herein, anti-RSV and or anti-RSV/anti-HMPF cross neutralizing antibodies by be obtained through B cell sorting techniques available to the artisan, and, for example, as described in the EXAMPLES below. Methods for generating human antibodies in transgenic mice are also known in the art and may be employed in order to derive antibodies in accordance with the present disclosure. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to RSV-F (see, for example, U.S. Pat. No. 6,596,541).

In certain embodiments, the antibodies of the instant invention possess affinities (K_(D)) ranging from about 1.0×10⁻⁷ M to about 1.0×10¹²M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M to about 6×10⁻¹⁰ M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M to about 9×10⁻¹⁰ M, when measured by binding to antigen either immobilized on solid phase or in solution phase.

The anti-RSV-F and/or anti-HMPV antibodies and antibody fragments disclosed herein encompass proteins having amino acid sequences that vary from those of the described antibodies, but that retain the ability to bind RSV-F. Such variant antibodies and antibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Likewise, the antibody-encoding DNA sequences of the present invention encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an antibody or antibody fragment that is essentially bioequivalent to an antibody or antibody fragment of the invention.

Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.

In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.

In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.

Bioequivalence may be demonstrated by in vivo and/or in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.

Bioequivalent variants of the antibodies of the invention may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include antibody variants comprising amino acid changes, which modify the glycosylation characteristics of the antibodies, e.g., mutations that eliminate or remove glycosylation.

Biological and Biophysical Characteristics of the Antibodies

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical, and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such antibodies also possess at least one, two, three, four, five, six, seven, eight, nine, ten, or more characteristics disclosed in the immediately following eleven paragraphs.

Without wishing to be bound by any theory, it is believed that the inventive antibodies and antigen-binding fragments thereof may function by binding to RSV-F, preferably in the PreF conformation, and in so doing act to block the fusion of the viral membrane with the host cell membrane. The antibodies of the present invention may also function by binding to RSV-F and in so doing block the cell to cell spread of the virus and block syncytia formation associated with RSV infection of cells. Advantageously, both RSV subtype A and RSV subtype B are effectively blocked, or neutralized, by the majority of the anti-RSV antibodies disclosed herein.

In certain embodiments, the inventive antibodies and antigen-binding fragment thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form of RSV-F.

In certain other embodiments, the inventive antibodies and antigen-binding fragments thereof advantageously display a clean or low polyreactivity profile (see, e.g., WO 2014/179363 and Xu et al., Protein Eng Des Sel, October; 26(10):663-70), and are thus particularly amenable to development as safe, efficacious, and developable therapeutic and/or prophylactic anti-RSV and/or HMPV treatments.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof, without wishing to be bound by any theory, may function by blocking or inhibiting RSV fusion to the cell membrane by binding to any one or more of, e.g., antigenic Sites ø, I, II, III, IV, or Site V of the PreF conformation of the F protein. In certain embodiments, the inventive antibodies display antigenic site specificity for Site ø, Site V, or Site III of PreF relative to RSV-F Site I, Site II, or Site IV.

In certain embodiments, at least a portion of the epitope with which the inventive antibodies and antigen-binding fragments thereof interacts comprises a portion of the α3 helix and β3/β4 hairpin of PreF. In certain embodiments, substantially all of the epitope of such antibodies comprises the α3 helix and β3/β4 hairpin of PreF. In still further embodiments, the inventive antibodies cross-compete with antibodies that recognize a portion or substantially all of the α3 helix and β3/β4 hairpin of PreF.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 μg/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml.

In certain embodiments, the binding affinity and/or epitopic specificity of the inventive antibodies and antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV) as well as RSV. In certain such embodiments, the inventive antibodies and antigen-binding fragments thereof comprise at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from the group consisting of Antibody Number 4, 11, and 62 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, motavizumab, or AM-14. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with palivisumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with motavizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof complete with one or more of D25, MPE8, palivisumab, motavizumab, and/or AM-14.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC₅₀) than D25 and/or palivizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise any combination of two, three, four, five, or six characteristics disclosed in the immediately preceding paragraphs, i.e., a) the anti-RSV F antibody cross-competes with an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6 for binding to RSV-F; b) the anti-RSV F antibody displays better binding affinity for the PreF form of RSV-F relative to the PostF form of RSV-F; c) the anti-RSV F antibody displays a clean or low polyreactivity profile; d) the anti-RSV F antibody displays neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the anti-RSV F antibody displays antigenic site specificity for RSV-F at Site ø, Site I, Site II, Site III, Site IV, or Site V; f) the anti-RSV F antibody displays antigenic site specificity for RSV-F Site ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the anti-RSV F antibody interacts comprises the α3 helix and β3/β4 hairpin of PreF; h) the anti-RSV F antibody displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 μg/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml; i) the binding affinity and/or epitopic specificity of the anti-RSV F antibody for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of anti-RSV F antibody for RSV-F or RSV-F DS-Cav1; j) the anti-RSV F antibody displays a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV); k) the anti-RSV F antibody does not complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or 1) the anti-RSV F antibody displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC₅₀) than D25 and/or palivizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence and a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof are each selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise are each selected from the group consisting of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

In certain embodiments, isolated nucleic acid sequences are provided that encode antibodies or antigen binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein and antigen-binding fragments thereof, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or at least 100% identical and/or all percentages of identity in between; to at least one the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH3 amino acid sequence of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH2 amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH1 amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL3 amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL2 amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL1 amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6, i.e., have identity across six CDRs with one of the antibodies of the invention.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (HC) amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the HC CDR amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the light chain (LC) amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the LC CDR amino acid sequences of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences are each selected from the group consisting of sequences that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; at least 100% identical, and/or all percentages of identity in between; to any one of the nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, the nucleic acid sequences of the invention may be modified according to methods known in the art. In other embodiments, the nucleic acid sequences of the invention may be present in or complexed with an art recognized carrier, e.g., a lipid nanoparticle, a polymeric nanomicelle, a linear or branched polymer or a lipid/lipid-like material.

In certain embodiments, expression vectors are provided comprising the isolated nucleic acid sequences disclose herein and throughout, and in particular in the immediately preceding paragraphs.

In certain embodiments, host cells transfected, transformed, or transduced with the nucleic acid sequences and/or the expression vectors disclosed immediately above are provided.

Epitope Mapping and Related Technologies

As described above and as demonstrated in the EXAMPLES, Applicant has characterized the epitopic specificities, bin assignments, and antigenic site assignments of the inventive antibodies and antigen-binding fragments thereof. In addition to the methods for conducting such characterization, various other techniques are available to the artisan that can be used to carry out such characterization or to otherwise ascertain whether an antibody “interacts with one or more amino acids” within a polypeptide or protein. Exemplary techniques include, for example, a routine cross-blocking assay such as that described Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., N.Y.) can be performed. Other methods include alanine scanning mutational analysis, peptide blot analysis (Reineke (2004) Methods Mol Biol 248:443-63), peptide cleavage analysis crystallographic studies and NMR analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. In general terms, the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein/antibody complex is transferred to water and exchangeable protons within amino acids that are protected by the antibody complex undergo deuterium-to-hydrogen back-exchange at a slower rate than exchangeable protons within amino acids that are not part of the interface. As a result, amino acids that form part of the protein/antibody interface may retain deuterium and therefore exhibit relatively higher mass compared to amino acids not included in the interface. After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues that correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267 (2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

As the artisan will understand, an epitope can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.

Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (U.S. Publ. No. 2004/0101920). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the antibodies of the invention into groups of antibodies binding different epitopes.

In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in one or more of the F protein patch variants disclosed, e.g., in the EXAMPLES and which are depicted in, e.g., FIG. 7A and which are designated as RSV F Variants 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG. In certain embodiments, such inventive antibodies and antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in RSV F Variant 2. In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with amino acid residues that extend beyond the region(s) identified above by about 5 to 10 amino acid residues, or by about 10 to 15 amino acid residues, or by about 15 to 20 amino acid residues towards either the amino terminal or the carboxy terminal of the RSV-F protein.

In certain embodiments, the antibodies of the present invention do not bind to the same epitope on RSV-F protein as palivizumab, motavizumab, MPE8, or AM-14.

As the artisan understands, one can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-RSV-F antibody by using routine methods available in the art. For example, to determine if a test antibody binds to the same epitope as a reference RSV-F antibody of the invention, the reference antibody is allowed to bind to a RSV-F protein or peptide under saturating conditions. Next, the ability of a test antibody to bind to the RSV-F molecule is assessed. If the test antibody is able to bind to RSV-F following saturation binding with the reference anti-RSV-F antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-RSV-F antibody. On the other hand, if the test antibody is not able to bind to the RSV-F molecule following saturation binding with the reference anti-RSV-F antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference anti-RSV-F antibody of the invention.

To determine if an antibody competes for binding with a reference anti-RSV-F antibody, the above-described binding methodology is performed in two orientations: In a first orientation, the reference antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the test antibody to the RSV-F molecule. In a second orientation, the test antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the reference antibody to the RSV-F molecule. If, in both orientations, only the first (saturating) antibody is capable of binding to the RSV-F molecule, then it is concluded that the test antibody and the reference antibody compete for binding to RSV-F. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the identical epitope as the reference antibody, but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope.

Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. (1990) 50:1495-1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art.

Immunoconjugates

The invention encompasses a human RSV-F monoclonal antibody conjugated to a therapeutic moiety (“immunoconjugate”), such as an agent that is capable of reducing the severity of primary infection with RSV and/or HMPV, or to ameliorate at least one symptom associated with RSV infection and/or HMPV infection, including coughing, fever, pneumonia, or the severity thereof. Such an agent may be a second different antibody to RSV-F and/or HMPV, or a vaccine. The type of therapeutic moiety that may be conjugated to the anti-RSV-F antibody and/or anti-HMPV antibody and will take into account the condition to be treated and the desired therapeutic effect to be achieved. Alternatively, if the desired therapeutic effect is to treat the sequelae or symptoms associated with RSV and/or HMPV infection, or any other condition resulting from such infection, such as, but not limited to, pneumonia, it may be advantageous to conjugate an agent appropriate to treat the sequelae or symptoms of the condition, or to alleviate any side effects of the antibodies of the invention. Examples of suitable agents for forming immunoconjugates are known in the art, see for example, WO 05/103081.

Multi-Specific Antibodies

The antibodies of the present invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The antibodies of the present invention can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked {e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multi-specific antibody with a second binding specificity.

An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first and second Ig C_(H)3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig C_(H)3 domain binds Protein A and the second Ig C_(H)3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second C_(H)3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second C_(H3) include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.

Therapeutic Administration and Formulations

The invention provides compositions (including pharmaceutical compositions) comprising the inventive anti-RSV-F and/or HMPV antibodies or antigen-binding fragments thereof or nucleic acid molecules encoding such antibodies or antigen-binding fragments thereof. The administration of compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-31 1.

The dose of each of the antibodies of the invention may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the antibodies of the present invention are used for treating a RSV infection and/or HMPV infection in a patient, or for treating one or more symptoms associated with a RSV infection and/or HMPV infection, such as the cough or pneumonia associated with a RSV infection and/or HMPV in a patient, or for lessening the severity of the disease, it is advantageous to administer each of the antibodies of the present invention intravenously or subcutaneously normally at a single dose of about 0.01 to about 30 mg/kg body weight, more preferably about 0.1 to about 20 mg/kg body weight, or about 0.1 to about 15 mg/kg body weight, or about 0.02 to about 7 mg/kg body weight, about 0.03 to about 5 mg/kg body weight, or about 0.05 to about 3 mg/kg body weight, or about 1 mg/kg body weight, or about 3.0 mg/kg body weight, or about 10 mg/kg body weight, or about 20 mg/kg body weight. Multiple doses may be administered as necessary. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. In certain embodiments, the antibodies or antigen-binding fragments thereof of the invention can be administered as an initial dose of at least about 0.1 mg to about 800 mg, about 1 mg to about 600 mg, about 5 mg to about 300 mg, or about 10 mg to about 150 mg, to about 100 mg, or to about 50 mg. In certain embodiments, the initial dose may be followed by administration of a second or a plurality of subsequent doses of the antibodies or antigen-binding fragments thereof in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings {e.g., oral mucosa, nasal mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. It may be delivered as an aerosolized formulation (See U.S. Publ. No. 2011/031 1515 and U.S. Publ. No. 2012/0128669). The delivery of agents useful for treating respiratory diseases by inhalation is becoming more widely accepted (See A. J. Bitonti and J. A. Dumont, (2006), Adv. Drug Deliv. Rev, 58:1 106-1118). In addition to being effective at treating local pulmonary disease, such a delivery mechanism may also be useful for systemic delivery of antibodies (See Maillet et al. (2008), Pharmaceutical Research, Vol. 25, No. 6, 2008).

The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see, for example, Langer (1990) Science 249:1527-1533).

In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but certainly are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUIIVIALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™ OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but certainly are not limited to the SOLOSTAR™ pen (Sanofi-Aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.) and the HUMIRA™ Pen (Abbott Labs, Abbott Park, Ill.), to name only a few.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.

Administration Regimens

According to certain embodiments, multiple doses of an antibody to RSV-F and/or HMPV, or a pharmaceutical composition comprising or encoding for these antibodies, may be administered to a subject over a defined time course. The methods according to this aspect of the invention comprise sequentially administering to a subject multiple doses of an antibody to RSV-F and/or HMPV, or sequentially administering to a subject multiple doses of a pharmaceutical composition comprising or encoding for an antibody of the invention or antigen binding fragment thereof. In one embodiment, nucleic acid sequences encoding for a heavy chain or light chain of an antibody of the invention (or antigen binding fragment thereof) are administered separately such that an antibody or antigen binding fragment thereof is expressed in the subject. In another embodiment, nucleic acid sequences encoding for a heavy chain and light chain of an antibody of the invention (or antigen binding fragment thereof) are administered together. As used herein, “sequentially administering” means that each dose of antibody to RSV-F and/or HMPV, or the pharmaceutical composition, is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient a single initial dose of an antibody to RSV-F and/or HMPV, or a composition comprising or encoding for the antibodies, followed by one or more secondary doses of the antibody to RSV-F and/or HMPV, or the composition, and optionally followed by one or more tertiary doses of the antibody to RSV-F and/or HMPV, or the composition.

The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the antibody to RSV-F and/or HMPV or the compositions of the invention. Thus, the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of antibody to RSV-F and/or HMPV, or nucleic acid sequence encoding at least one chain of such antibody (or antigen binding fragment thereof), but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of antibody to RSV-F and/or HMPV, or nucleic acid sequence encoding at least one chain of such antibody (or antigen binding fragment thereof), contained in the initial, secondary and/or tertiary doses vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses”).

In one exemplary embodiment of the present invention, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks after the immediately preceding dose. The phrase “the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of antibody to RSV-F and/or HMPV, or nucleic acid sequence encoding at least one chain of such antibody (or antigen binding fragment thereof), which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

The methods according to this aspect of the invention may comprise administering to a patient any number of secondary and/or tertiary doses of an antibody to RSV-F and/or HMPV or a nucleic acid sequence(s) encoding at least one chain of such antibody (or antigen binding fragment thereof). For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

Accordingly, in certain embodiments are provided pharmaceutical compositions comprising: one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout and a pharmaceutically acceptable carrier and/or one or more excipients. In certain other embodiments are provided pharmaceutical compositions comprising: one or more nucleic acid sequences encoding one or more inventive antibodies or antigen-binding fragments thereof, e.g., a nucleic acid sequence(s) encoding one or more chains of an antibody or antigen-binding fragment thereof as disclosed herein; or one or more the expression vectors harboring such nucleic acid sequences; and a pharmaceutically acceptable carrier and/or one or more excipients.

Therapeutic Uses of the Antibodies and Pharmaceutical Compositions

Due to their binding to and interaction with the RSV fusion protein (RSV-F), it is believed that the inventive antibodies and antigen-binding fragments thereof, and pharmaceutical compositions encoding or comprising such antibodies, are useful—without wishing to be bound to any theory—for preventing fusion of the virus with the host cell membrane, for preventing cell to cell virus spread, and for inhibition of syncytia formation. Additionally, as Applicant has demonstrated herein that, surprisingly, a subset of the inventive anti-RSV antibodies and antigen-binding fragment thereof display cross-neutralizing potency against HMPV, the inventive antibodies and antigen-binding fragments thereof and pharmaceutical compositions are advantageous for preventing an infection of a subject with RSV and/or HMPV when administered prophylactically. Alternatively, the antibodies and pharmaceutical compositions of the present invention may be useful for ameliorating at least one symptom associated with the infection, such as coughing, fever, pneumonia, or for lessening the severity, duration, and/or frequency of the infection. The antibodies and pharmaceutical compositions of the invention are also contemplated for prophylactic use in patients at risk for developing or acquiring an RSV infection and/or HMPV infection. These patients include pre-term infants, full term infants born during RSV season (late fall to early spring), the elderly (for example, in anyone 65 years of age or older) and/or HMPV season, or patients immunocompromised due to illness or treatment with immunosuppressive therapeutics, or patients who may have an underlying medical condition that predisposes them to an RSV infection (for example, cystic fibrosis patients, patients with congestive heart failure or other cardiac conditions, patients with airway impairment, patients with COPD) and/or HMPV infection. It is contemplated that the antibodies and pharmaceutical compositions of the invention may be used alone, or in conjunction with a second agent, or third agent for treating RSV infection and/or HMPV infection, or for alleviating at least one symptom or complication associated with the RSV infection and/or HMPV infection, such as the fever, coughing, bronchiolitis, or pneumonia associated with, or resulting from such an infection. The second or third agents may be delivered concurrently with the antibodies (or pharmaceutical compositions) of the invention, or they may be administered separately, either before or after the antibodies (or pharmaceutical compositions) of the invention. The second or third agent may be an anti-viral such as ribavirin, an NSAID or other agents to reduce fever or pain, another second but different antibody that specifically binds RSV-F, an agent (e.g., an antibody) that binds to another RSV antigen, such as RSV-G, a vaccine against RSV, an siRNA specific for an RSV antigen.

In yet a further embodiment of the invention the present antibodies (or antigen binding fragments thereof) or nucleic acid sequence encoding at least one chain of such antibody (or antigen binding fragment thereof), are used for the preparation of a pharmaceutical composition for treating patients suffering from a RSV infection and/or HMPV infection. In yet another embodiment of the invention the present antibodies (or antigen-binding fragments thereof), or nucleic acid sequence encoding at least one chain of such antibody (or antigen binding fragment thereof), are used for the preparation of a pharmaceutical composition for reducing the severity of a primary infection with RSV and/or HMPV, or for reducing the duration of the infection, or for reducing at least one symptom associated with the RSV infection and/or the HMPV infection. In a further embodiment of the invention, the present antibodies (or pharmaceutical compositions comprising or encoding such antibodies) are used as adjunct therapy with any other agent useful for treating an RSV infection and/or and HMPV infection, including an antiviral, a toxoid, a vaccine, a second RSV-F antibody, or any other antibody specific for an RSV antigen, including an RSV-G antibody, or any other palliative therapy known to those skilled in the art.

Accordingly, in certain embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout (or pharmaceutical compositions of the invention), such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6 or nucleic acid sequence encoding at least one chain of such antibody or antigen binding fragment thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In certain other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding at least one of a light chain or heavy chain of one or more of the inventive antibodies or antigen-binding fragments thereof, such as the nucleic acid sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In one embodiment, a pharmaceutical composition of the invention comprises a nucleic acid sequence encoding an antibody light chain or antigen-binding fragment thereof and a nucleic acid sequence encoding an antibody heavy chain or antigen-binding fragment thereof. In another embodiment, a first pharmaceutical composition of the invention comprises a nucleic acid sequence encoding an antibody light chain (or antigen binding fragment thereof) and a second pharmaceutical composition comprises a nucleic acid sequence encoding an antibody heavy chain (or antigen binding fragment thereof) such that upon coadministration of the first and second pharmaceutical compositions to the subject, an antibody of the invention or antigen binding fragment thereof is expressed in the subject.

In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences encoding at least one of a light chain or a heavy chain of an antibody of the invention or an antigen binding fragment thereof or an expression vectors comprising such a nucleic acid sequence(s), wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising such one or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In certain embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout, such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, or pharmaceutical compositions comprising or encoding such antibodies or antigen-binding fragments thereof, e.g., one or more nucleic acid molecules encoding such antibodies, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof is selected from the group consisting of the antibodies designated as Antibody Number 4, 11, and 62 as disclosed in Table 6 or one or more nucleic acid molecules encoding such antibodies.

In certain other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, e.g., encoding heavy or light chains of the antibodies, such nucleic acid sequences disclosed in Table 6 and compliments thereof, such that the RSV infection and/or the HMPV infection is treated or prevented, or the at least on symptom associated with RSV and/or HMPV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof, e.g., antibody light or heavy chains, is selected from the group consisting of the antibodies designated as Antibody Number Antibody Number 4, 11, and 62 as disclosed in Table 6. In one embodiment, a pharmaceutical composition of the invention comprises a nucleic acid sequence encoding an antibody light chain or antigen-binding fragment thereof and a nucleic acid sequence encoding an antibody heavy chain or antigen binding fragment thereof. In another embodiment, a first pharmaceutical composition of the invention comprises a nucleic acid sequence encoding an antibody light chain (or antigen binding fragment thereof) and a second pharmaceutical composition comprises a nucleic acid sequence encoding an antibody heavy chain (or antigen binding fragment thereof) such that upon coadministration of the first and second pharmaceutical compositions to the subject, an antibody of the invention or antigen binding fragment thereof is expressed in the subject.

In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof of is selected from the group consisting of the antibodies designated as Antibody Number Antibody Number 4, 11, and 62 as disclosed in Table 6.

In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising such one or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof of is selected from the group consisting of the antibodies designated as Antibody Number Antibody Number 4, 11, and 62 as disclosed in Table 6.

Combination Therapies

As noted above, according to certain embodiments, the disclosed methods comprise administering to the subject one or more additional therapeutic agents in combination with an antibody to RSV-F and/or HMPV or a pharmaceutical composition of the invention. As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with the antibody or pharmaceutical composition of the invention. The term “in combination with” also includes sequential or concomitant administration of the anti-RSV-F antibody or pharmaceutical composition and a second therapeutic agent.

For example, when administered “before” the pharmaceutical composition comprising or encoding the anti-RSV-F and/or HMPV antibody, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the pharmaceutical composition comprising or encoding the anti-RSV-F and/or HMPV antibody. When administered “after” the pharmaceutical composition comprising or encoding the anti-RSV-F and/or HMPV antibody, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the pharmaceutical composition comprising or encoding the anti-RSV-F and/or HMPV antibodies. Administration “concurrent” or with the pharmaceutical composition comprising or encoding the anti-RSV-F and/or HMPV antibody means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising or encoding the anti-RSV-F and/or HMPV antibody, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the anti-RSV-F antibody or pharmaceutical composition.

Combination therapies may include an anti-RSV-F and/or HMPV antibody or pharmaceutical composition of the invention and any additional therapeutic agent that may be advantageously combined with an antibody of the invention, or with a biologically active fragment of an antibody of the invention.

For example, a second or third therapeutic agent may be employed to aid in reducing the viral load in the lungs, such as an antiviral, for example, ribavirin. The antibodies or pharmaceutical compositions of the invention may also be used in conjunction with other therapies, as noted above, including a toxoid, a vaccine specific for RSV and/or HMPV, a second antibody specific for RSV-F, or an antibody specific for another RSV antigen, such as RSV-G.

Diagnostic Uses of the Antibodies

The inventive anti-RSV and/or HMPV antibodies and antigen-binding fragments thereof may also be used to detect and/or measure RSV and/or HMPV in a sample, e.g., for diagnostic purposes. It is envisioned that confirmation of an infection thought to be caused by RSV and/or HMPV may be made by measuring the presence of the virus through use of any one or more of the antibodies of the invention. Exemplary diagnostic assays for RSV and/or HMPV may comprise, e.g., contacting a sample, obtained from a patient, with an anti-RSV-F and/or HMPV antibody of the invention, wherein the anti-RSV-F and/or HMPV antibody is labeled with a detectable label or reporter molecule or used as a capture ligand to selectively isolate the virus containing the F protein from patient samples. Alternatively, an unlabeled anti-RSV-F and/or HMPV antibody can be used in diagnostic applications in combination with a secondary antibody which is itself detectably labeled. The detectable label or reporter molecule can be a radioisotope, such as ³H, ¹⁴C, ³²P ³⁵S, or ¹²⁵I; a fluorescent or chemiluminescent moiety such as fluorescein isothiocyanate, or rhodamine; or an enzyme such as alkaline phosphatase, 0-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure RSV containing the F protein and/or HMPV in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).

Samples that can be used in RSV and/or HMPV diagnostic assays according to the present invention include any tissue or fluid sample obtainable from a patient, which contains detectable quantities of RSV-F protein and/or HMPV, or fragments thereof, under normal or pathological conditions. Generally, levels of RSV-F and/or HMPV in a particular sample obtained from a healthy patient (e.g., a patient not afflicted with a disease or condition associated with the presence of RSV-F and/or HMPV) will be measured to initially establish a baseline, or standard, level of the F protein from RSV and/or HMPV. This baseline level of RSV-F and/or HMPV can then be compared against the levels of RSV-F and/or HMPV measured in samples obtained from individuals suspected of having an RSV and/or HMPV infection, or symptoms associated with such infection.

EXAMPLES

Applicant has comprehensively profiled the human antibody response to RSV fusion protein (F) by isolating and characterizing 123 RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult donor, and used these antibodies to comprehensively map the antigenic topology of RSV F. The antibody response to RSV F was determined to be comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV antibodies that target this region, as well as vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, this class of antibodies displayed convergent sequence features, thus providing a future means to rapidly detect these types of antibodies in human samples. Many of the antibodies that bound preF-specific surfaces from this donor were over 100 times more potent than palivizumab and several cross-neutralized human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine and antibody-based therapeutic candidates, and offer new options for passive prophylaxis.

Large-Scale Isolation of RSV F-Specific Monoclonal Antibodies from Healthy Adult Human Donors

In order to comprehensively profile the human antibody response to RSV F, Applicant isolated and characterized 123 monoclonal antibodies from the memory B cells of a healthy adult donor (“donor 076”). Although this donors did not have a documented history of RSV infection, healthy adults are expected to have had multiple RSV infections throughout life (26).

The magnitude of the memory B cell response in this donor to RSV F was assessed by staining peripheral B cells with a mixture of fluorescently labeled pre- and postfusion RSV F sorting probes (FIG. 6A through 6B) (11, 15). Both proteins were dual-labeled in order to eliminate background due to non-specific fluorochrome binding (27). Flow cytometric analysis revealed that 0.04-0.18% of class-switched (IgG⁺ and IgA⁺) peripheral B cells were specific for RSV F (FIG. 1A and Figure B), which is significantly lower than the percentage of RSV F-specific cells observed after experimental RSV infection and suggests that this donor was probably not recently exposed to RSV (28). Notably, index sorting showed that 17-38% of circulating RSV F-specific B cells express IgA, indicating that IgA memory B cells to RSV F are present in peripheral blood (FIG. 1B).

Approximately 200 RSV F-specific B cells were single-cell sorted from the donor sample, and antibody variable heavy (VH) and variable light (VL) chain genes were rescued by single-cell PCR (29). One hundred twenty-three (123) cognate heavy and light chain pairs were subsequently cloned and expressed as full-length IgGs in an engineered strain of Saccharomyces cerevisiae for further characterization (30). Preliminary binding studies showed that approximately 80% of antibodies cloned from RSV F glycoprotein (F)-specific B cells bound to recombinant RSV F proteins.

Sequence Analysis of RSV F-Specific Antibody Repertoires

Sequence analysis of the isolated monoclonal antibodies revealed that the RSV-F specific repertoire was highly diverse, containing over 70 unique lineages (FIG. 1C and Table 2). This result is in stark contrast to the relatively restricted repertoires observed in HIV-infected patients (31), or in healthy donors after influenza vaccination (32). Compared to non-RSV-reactive antibodies (33), the RSV F-specific repertoires were skewed, generally, toward certain VH germline genes (VH1-18, VH1-2, VH1-69, VH3-21, VH3-30, VH4-304, and VH5-51) (FIG. 1D and Table 2) and longer heavy chain third complementarity-determining region (CDRH3) lengths (generally, approximately 14-18 amino acids in length; FIG. 1E and Table 2). Interestingly, a bias toward VH1-69 has also been observed in anti-HIV-1, anti-influenza, and anti-HCV repertoires (34-36), and recent studies have shown that there is a significant increase in the relative usage of VH1-18, VH1-2, and VH1-69 during acute dengue infection (37). Hence, it appears that these particular germline gene segments may have inherent properties that facilitate recognition of viral envelope proteins.

The average level of somatic hypermutation (SHM) ranged generally between 16 and 30 nucleotide substitutions per VH gene (excluding CDRH3) (FIG. 1F and Table 2), which is comparable to the average level of SHM observed in anti-influenza antibody repertoires (32, 38) and consistent with the recurrent nature of RSV infection (26). Interestingly, several antibodies contained 60 or greater VH gene nucleotide substitutions, suggesting that multiple rounds of RSV infection can result in antibodies with very high levels of somatic hypermutation (SHM).

A Large Proportion of Antibodies Bind Exclusively to preF

We next measured the apparent binding affinities of the IgGs to furin-cleaved RSV F ectodomains stabilized in the prefusion (DS-Cav1) or postfusion (F ΔFP) conformation using biolayer interferometry (11, 15). A relatively large proportion of the antibodies (36-67%) bound exclusively to preF (FIG. 2A and Figure B; Table 3). The vast majority of remaining antibodies bound to both pre- and postF, with only 5-7% of antibodies showing exclusive postF specificity (FIG. 2A and Figure B; Table 3). The low prevalence of postF-specific antibodies in these donor repertoires is consistent with the observation that less than 10% of anti-RSV F serum-binding activity specifically targets postF (8). Interestingly, however, the majority of cross-reactive antibodies bound with higher apparent affinity to postF (FIG. 2A; Table 3), suggesting that these antibodies were probably elicited by and/or affinity matured against postF in vivo. Hence, the significantly higher proportion of preF- versus postF-specific antibodies is likely due to the higher immunogenicity of the unique surfaces on preF compared to postF, rather than an increased abundance of preF in vivo. Finally, as expected based on the relatively high degree of sequence conservation between RSV subtypes, most of the antibodies showed binding reactivity to F proteins derived from both subtypes A and B (FIG. 2C; Table 3).

Since certain antiviral antibody specificities have been associated with poly- and autoreactivity (39-41), we also tested the RSV antibodies for polyreactivity using a previously described high-throughput assay that correlates with down-stream behaviors such as serum clearance (42, 43). One hundred and seventy-seven clinical antibodies, as well as several broadly neutralizing HIV antibodies, were also included for comparison. Interestingly, in contrast to many previously described HIV broadly neutralizing antibodies, the vast majority of RSV F-specific antibodies lacked significant polyreactivity in this assay (FIG. 2D).

RSV F-Specific Antibodies Target Six Major Antigenic Sites

To map the antigenic specificities of the RSV F-specific antibodies, Applicant first performed competitive binding experiments using a previously described yeast-based assay (44). Antibodies were initially tested for competition with D25, AM14 and MPE8—three previously described preF-specific antibodies (10, 17, 21)—and motavizumab, an affinity-matured variant of palivizumab that binds to both pre- and postF (10, 11, 45). Non-competing antibodies were then tested for competition with a site IV-directed mAb (101F) (46), a site I-directed antibody (Site I Ab), and two high affinity antibodies (High Affinity Ab I and High Affinity Ab 2, respectively) that did not strongly compete with each other or any of the control antibodies. Each antibody was assigned a bin based on the results of this competition assay (see, e.g., Table 4).

In order to confirm and increase the resolution of our epitope assignments, the binding of each antibody to a panel of preF variants was measured using a luminex-based assay. Each variant contained 2-4 mutations clustered together to form a patch on the surface of preF. A total of nine patches that uniformly covered the surface of preF were generated (FIG. 7A through FIG. 7C). Deglycosylated preF was also included to identify antibodies targeting glycan-dependent epitopes. Binding of each antibody to the 10 preF variants was compared to that of wild-type preF and used to assign a patch (see, e.g., Table 4). Previously characterized antibodies D25, AM14 and motavizumab were used to validate the assay (see, e.g., FIG. 7C and Table 4). The combined bin and patch data were then used to assign each antibody to a single antigenic site (FIG. 3A through FIG. 3G), which were defined based on previously determined structures, resistance mutations, and secondary structure elements of the F protein. Overall, these data show that the large majority of isolated antibodies target six dominant antigenic sites on prefusion RSV F (ø, I, II, III, IV, and V). Interestingly, only a small proportion of the isolated antibodies had binding profiles similar to that of AM14, suggesting that antibodies targeting this quaternary epitope are not commonly elicited during natural infection. None of the antibodies were sensitive to deglycosylation of F, demonstrating that glycan-dependent antibodies are also rarely elicited by natural RSV infection.

Analysis of the preF- and postF-binding activities of the antibodies targeting each antigenic site (see, e.g., FIG. 3C through FIG. 3G; Table 4) revealed that three sites are primarily found on preF (ø, III, and V). Antibodies targeting site ø and site III have been previously described (10, 17), and these sites are located on the top and side of the preF spike, respectively. Approximately 4% of the antibodies from this donor recognized site ø and approximately 6% recognized site III. A relatively large proportion of antibodies from this donor (approximately 20%) recognized the third preF-specific site, which has not been previously described and therefore has been designated herein as region site V (See, e.g., FIG. 3C through FIG. 3G; Table 4). The majority of site V antibodies competed with D25, MPE8 and motavizumab, which was unexpected given the distance between the epitopes recognized by these three antibodies. The patch mutant analysis revealed that these antibodies interact with the α3 helix and β3/β4 hairpin of preF. This region is located between the epitopes recognized by D25, MPE8, and motavizumab, explaining the unusual competition profile observed for this class of antibodies (See, e.g., FIG. 8). In addition to the three primarily preF-specific sites, a large number of the antibodies that recognized antigenic site IV were preF-specific, likely due to contacts with β22, which dramatically rearranges during the transition from pre- to postF. In summary, the epitope mapping data show that the large majority of isolated antibodies target six dominant antigenic sites, approximately half of which are exclusively expressed on preF.

Highly Potent Neutralizing Antibodies Target preF-Specific Epitopes

The antibodies were next tested for neutralizing activity against RSV subtypes A and B using a previously described high-throughput neutralization assay (15). Greater than 60% of the isolated antibodies showed neutralizing activity, and approximately 20% neutralized with high potency (IC₅₀≤0.05 μg/ml) (see, e.g., FIG. 4A and FIG. 4B; Table 3). Notably, several clonally unrelated antibodies were ≥5.0-fold more potent than D25 and ≥100-fold more potent than palivizumab (see, e.g., FIG. 4A; Table 3). Interestingly, there was no correlation between neutralization potency and level of SHM, suggesting that extensive SHM is not required for potent neutralization of RSV. Consistent with the binding cross-reactivity data, the majority of neutralizing antibodies showed activity against both subtype A and B (FIG. 4A through FIG. 4C; Table 3).

The relationship between preF- and postF-binding affinity and neutralization potency was next investigated, which clearly demonstrated that the majority of highly potent antibodies bound preferentially or exclusively to preF (see, e.g., FIG. 4D through FIG. 4G; Table 3). Quantifying this difference revealed that more than 80% of highly potent antibodies (IC₅₀<0.05 μg/ml) were specific for preF (See, e.g., FIG. 9; Table 3) and that the median IC₅₀ for preF-specific antibodies was more than 8-fold lower than for pre- and postF cross-reactive antibodies and 80-fold lower than antibodies that specifically recognized postF (see, e.g., FIG. 4E; Table 3). Importantly, there was a positive correlation between preF binding and neutralization (P<0.001, r=0.24), and the apparent preF K_(D)s generally corresponded well with the neutralization IC₅₀s (see, e.g., FIG. 5A; Table 3). In contrast, there was no correlation between neutralization potency and postF affinity (P=0.44, r=−0.07) (see, e.g., FIG. 5B; Table 3). This result is compatible with the occupancy model of antibody-mediated neutralization (47), and suggests that DS-Cav1 is a faithful antigenic mimic of the native preF trimer. Notably, very few antibodies neutralized with IC₅₀s lower than 100 pM, which is consistent with the previously proposed ceiling to affinity maturation (48, 49).

The relationship between neutralization potency and antigenic site was next analyzed. The results, provided in, e.g., FIG. 5C, Table 3, and Table 4, collectively, indicated that over 60% of the highly potent neutralizing antibodies targeted antigenic sites ø and V, which are two of the three prefusion-F specific sites. In contrast, antibodies targeting sites III and IV showed a wide range of neutralization potencies, and antibodies targeting sites I and II were generally moderate to non-neutralizing. Similar results were obtained using binding affinities and neutralization potencies measured for subtype B (See, e.g., FIG. 10A through FIG. 10C; Table 3 and Table 4). Interestingly, a subset of site IV-directed antibodies neutralized with substantially lower potency than would be expected based on preF binding affinity (see, e.g., FIG. 5A; Table 3). This result may suggest that certain epitopes within site IV are less exposed in the context of the native envelope spike expressed on the crowded surface of the virion than on recombinant preF.

Several Antibodies Cross-Neutralize RSV and HMPV

Given that the RSV and human metapneumovirus (HMPV) F proteins share 33% amino acid identity, and certain RSV F-specific antibodies cross-neutralize HMPV (17, 50), the antibodies from this donor were tested for neutralizing activity against HMPV. Of the 123 antibodies tested, three neutralized HMPV (see, e.g., Table 5). Sequence analysis revealed that the three antibodies represent two different clonal families, which utilize different VH germline genes and have varying CDRH3 lengths and levels of somatic hypermutation (See, e.g., Table 2 and sequence listing). All of the cross-neutralizing antibodies bound exclusively to preF and competed with MPE8 (See, e.g., Table 5), in agreement with previous studies indicating that MPE8 cross-neutralizes four pneumoviruses, including RSV and HMPV (17). This result suggests, inter alia, that highly conserved epitopes are relatively immunogenic in the context of natural RSV and/or HMPV infection.

Discussion

An in-depth understanding of the human antibody response to RSV infection will aid the development and evaluation of RSV vaccine and therapeutic and/or prophylactic antibody candidates for the treatment and/or prevention of RSV infection. Although previous studies have coarsely mapped the epitopes targeted by RSV-specific neutralizing antibodies in human sera (4, 8), the specificities and functional properties of antibodies induced by natural RSV infection have remained largely undefined. As disclosed herein, preF- and postF-stabilized proteins (11, 15), a high-throughput antibody isolation platform, and a structure-guided collection of prefusion F mutants, were used to clonally dissect the human memory B cell response to RSV F in a naturally infected adult donor, and highly potent and selective RSV-neutralizing—as well as highly potent anti-RSV/anti-HMPV cross-selective and cross-neutralizing—were isolated and characterized.

In the repertoire analyzed, the ratio of preF-specific antibodies to those that recognize both pre- and postF was slightly greater than 1:1 (See, e.g., FIG. 2B). These values are somewhat lower than those reported for human sera, which showed approximately 70% of anti-F serum binding is specific for preF (8). This discrepancy may be the result of differences between the levels of individual antibodies in serum, differences in the B cell phenotypes achieved for a particular specificity, or variation between donors. Despite these minor differences, the results of both studies suggest that preF-specific epitopes and epitopes shared by pre- and postF are immunogenic during natural RSV infection, whereas the unique surfaces on postF are significantly less immunogenic.

The repertoire analysis disclosed herein revealed that the large majority of RSV F-specific antibodies target six dominant antigenic sites on prefusion RSV F: øI, II, III, IV, and V. These sites were defined based on previously determined structures, epitope binning/competition assays, resistance mutations, and secondary structure elements of the preF protein. It is important to note that the nomenclature for describing RSV F antigenic sites has evolved over time (6, 51-57), and previous mapping efforts were based on the postfusion conformation of F and did not include surfaces present exclusively on preF. The crystal structure of preF has provided critical information about F structure and function as well as new reagents to map antibody binding sites on the unique surfaces of preF and surfaces shared with postF. To a first approximation, each antibody can be assigned primarily to one of these sites. However, it is likely that antibody epitopes cover the entire surface of F and that there are antibodies that bind two or more adjacent antigenic sites within a protomer and quaternary antibodies that bind across protomers.

Importantly, the results disclosed herein show that the most potently neutralizing antibodies target antigenic sites ø and V, both of which are located near the apex of the preF trimer. These findings are consistent with results obtained from human sera mapping, which determined that the majority of neutralizing activity can be removed by pre-incubation with preF (4, 8) and that preF-specific sites other than site ø make up a considerable fraction of preF-specific neutralizing antibodies (8). Although antigenic site ø has been shown to be a target of potently neutralizing antibodies (8, 10), the interaction of antibodies with site V is less well understood. Interestingly, it was found that the majority of site V-directed antibodies share several convergent sequence features, suggesting that it may be possible to rapidly detect these types of antibodies in human samples using high-throughput sequencing technology (58). Applicant anticipates this finding to be particularly advantageous in profiling antibody responses to RSV vaccine candidates that aim to preserve the apex of the preF trimer.

The extensive panel of antibodies described here provides new opportunities for passive prophylaxis, as well as for treatment of RSV infection. A large number of these antibodies neutralize RSV more potently than D25, which serves as the basis for MEDI8897—a monoclonal antibody that is currently in clinical trials for the prevention of RSV in young, at risk children (59). Additionally, a subset of these antibodies were demonstrated to cross-neutralize HMPV.

The development of an effective RSV vaccine has presented a number of unique challenges, and selection of the optimal vaccination strategy will be of the utmost importance. The in-depth analysis of the human antibody response to natural RSV infection presented here provides insights for the development of such a vaccine. Importantly, the results suggest that immunization of pre-immune donors with preF immunogens would be expected to boost neutralizing responses, whereas the use of postF immunogens would likely expand B cell clones with moderate or weak neutralizing activity. Similarly, immunization of RSV naïve infants with preF immunogens would be expected to activate naïve B cells targeting epitopes associated with substantially more potent neutralizing activity compared to postF immunogens. In addition, the ideal RSV vaccine should preserve antigenic sites ø and V, since these sites are targeted by the most highly potent antibodies elicited in response to natural RSV infection.

Accordingly, disclosed herein are highly selective and potent anti-RSV antibodies, nucleic acids molecules encoding these antibodies, as well as highly potent cross-neutralizing anti-RSV and anti-HMPV antibodies, as well as vaccine candidates, for the treatment and or prophylaxis of RSV and/or HMPV infection. Additionally, the reagents disclosed here provide a useful set of tools for the evaluation of clinical trials, which will be critical for selecting the optimal RSV vaccination or antibody-based therapeutic strategy from the many currently under investigation (60).

TABLE 1 Antigenic sites targeted by prototypic RSV antibodies Antigenic site Prototypic antibodies Ø D25, 5C4, AM22 (10,16) I 131-2a, 2F II 1129, palivizumab, motavisumab (6) III MPE8 (17) IV 101F (57), mAb 19 (19)

TABLE 2 Germline usage and sequence information of anti-RSV antibodies VH LC Number of Number of Antibody germline germline nucleotide nucleotide number gene gene CDR H3 CDR L3 Lineage substitutions substitutions Name (Ab #) usage usage Sequence Sequence number in VH in VL ADI- 1 VH1-8 VK1-5 ARPDIN QQYKS 38 31 13 14438 WGQDA DPT FDV ADI- 2 VH1-69 VK3-20 AIIDPQ QQYGS 3 42 16 14439 DCTAA APIT SCFWV NWLDP ADI- 3 VH1-69 VK3-20 AIIDPQ QQFGA 3 31 14 14440 LCTRAS LPIT CFWVN WLDP ADI- 4 VH1-69 VK3-15 ATAGW QQYNN 54 29 2 14441 FGESVH WPPLT LDS ADI- 5 VH1-18 VK2-30 ARDVP MQGSH 22 15 6 14442 ADGVH WAPT FMDV ADI- 6 VH1-69 VK2-40 ATKRY MQRVE 56 20 3 14443 CSDPSC FPYT HGLWY FDL ADI- 7 VH1-46 VL2-14 ARIGSN CSFTSS 34 38 16 14444 EI GSRV ADI- 8 VH1-69 VK3-20 AIIDPQ QQYDS 3 43 16 14445 DCTRA APIT SCFWV NWLDP ADI- 9 VH1-69 VK2-40 ATKRY MQRIE 56 28 5 14446 CTSPSC YPYT HGLWY FNL ADI- 10 VH1-69 VK1-16 AGSLL QQYYI 1 29 12 14447 AGYDR YPLT EFDS ADI- 11 VH3-21 VL1-40 VRHMN QSYDRI 68 30 9 14448 LVMGP GMYV FAFDI ADI- 12 VH3-15 VL1-47 STGPPY AAWDD 60 13 17 14449 KYFDE NLSGPV TGYSV VDY ADI- 13 VH3-15 VL1-47 STGPPY AAWDD 60 25 16 14450 SYFDST SLSGPV GYSVV DY ADI- 14 VH1-2 VL3-19 ARSQQ NCRDSS 44 21 15 14451 LLVITD GHRLV YSLDY ADI- 15 VH1-69 VK2-40 ATKRY MQRVE 56 26 4 14452 CTSPSC YPYS HGLWY FNL ADI- 16 VH2-5 VK1-39 AHIGLY QHTYT 2 14 15 14453 DRGGY TPYI YLFYFDF ADI- 17 VH2-5 VK1-39 VHSDL QQAYS 65 13 12 14454 YDSGG APYT YYLYY FDY ADI- 18 VH1-18 VK2-30 ARDVP MQGPH 23 3 0 14455 VIAAGT WPRT MDY ADI- 19 VH1-2 VK1-39 AKDRA QQSFTI 6 32 13 14456 ASVHV PSIT PAGAF DL ADI- 20 VH2-70 VK1-39 ARTLY QQSYSS 46 29 20 14457 YTSGG TPT YYLNL FDY ADI- 21 VH3-15 VL1-47 TTGPPY ASWDD 60 12 15 14458 SYFDST SLSGPV GYSIVDY ADI- 22 VH3-15 VL1-47 STGPPY AMWD 60 7 7 14459 KYHDS DSLNGPV TGYSV VDY ADI- 23 VH4-34 VL2-14 TRSETS GSYTD 63 32 13 14460 DYFDSS TNRL GYAFHI ADI- 24 VH3-30 VL2-8 ARDQW SSYAGS 18 8 5 14461 LVPDY NSV ADI- 25 VH3-33 VL2-14 ATERM TSYTSR 55 19 8 14462 WEENS SSYV SSFGW ADI- 26 VH1-18 VK2-30 ARDVP MQGTH 24 31 16 14463 VMGAA WPPT FLDY ADI- 27 VH1-18 VK1-39 AKDRA QQSYTI 6 28 9 14464 ASVHV PSIT PAGEFDL ADI- 28 VH4-34 VL3-21 ARQRL QVWDN 40 30 22 14465 EHTAS SSDQPV GYYMDV ADI- 29 VH5-a VK4-1 ARHKE QQYFTS 32 18 20 14466 NYDFW TF DF ADI- 30 VH1-18 VK2-30 VRDVP MQATQ 67 20 3 14467 VISGAS WPRT TMDY ADI- 31 VH2-5 VK1-39 VKSDL QQTFSS 65 27 24 14468 YDRGG PYT YYLYY FDH ADI- 32 VH2-5 VK1-39 VKSDL QQTFSS 65 18 22 14469 YDRGG PYT YYLYY FDY ADI- 33 VH2-70 VK1-39 VRSSV QQAYS 70 13 12 14470 YASNA SPYT YYLYY FDS ADI- 34 VH1-69 VK2-40 ATKRY MQRAE 56 19 2 14471 CSDPSC FPYT HGLWY FDL ADI- 35 VH5-a VK4-1 ARHKE QQYYS 32 8 10 14473 NYDFW SAF DF ADI- 36 VH1-18 VK2-30 ARDVP MQGTH 24 35 14 14474 VMGAA WPPT FLDY ADI- 37 V H2-70 VK1-39 VRTPIY QQSYST 70 10 15 14475 ASGGY PYT YLSYFDS ADI- 38 VH2-5 VK1-39 VHSDR QQSYTS 65 17 15 14476 YDRGG PYT YYLYFF DY ADI- 39 VH2-5 VK1-39 VHSDL QQSYTF 65 15 14 14477 YDRGG PYT YYLFYF DD ADI- 40 VH3-11 VL1-40 ARDQR QSYDN 17 2 5 14478 DQAVA SLSGSAV GRWFDP ADI- 41 VH1-2 VK2-28 ARTMW MQALQ 47 23 2 14479 RWLVE TPLT GGFEN ADI- 42 VH1-69 VK3-15 ATAGW QQYNN 54 48 8 14480 FGELVR WPPLT FDS ADI- 43 VH4-34 VL3-21 ARASS QVWDD 8 22 11 14482 GTYNF PSDHAV EYWFDP ADI- 44 VH3-21 VL1-40 ARDWG QSYDR 26 29 2 14483 GHSIFG SLSQV AVQDL ADI- 45 VH2-70 VK1-39 ARTLY QQSYSS 46 29 20 14484 YTSGG TPT YYLNL FDY ADI- 46 VH1-69 VK3-15 ARPEG QQYDD 39 28 7 14485 DFGDL WPPQLT KWLRS PFDY ADI- 47 VH4- VL2-14 ARHPS SSYTGS 33 18 8 14486 304 VIYGTF NTVI GANGG PNWFDP ADI- 48 VH1-2 VK2-28 ARVTW MQALH 52 17 2 14487 QWLVL TPLT GGFDY ADI- 49 VH3-73 VL2-14 TLGYCS SSYTSS 62 11 1 14488 GDSCSS STLV LRDY ADI- 50 VH1-18 VK2-30 ARDVP MQGSH 22 14 6 14489 ADGVH WAPT FMDV ADI- 51 VH3-33 VL1-40 ARDAIF QSYESS 9 4 1 14490 GSGPN LRGWV WFDP ADI- 52 VH3-30 VL2-8 ARDQW SSYAGS 18 8 5 14491 LVPDY NSV ADI- 53 VH3-15 VL1-47 TTGPPY AAWDD 60 15 14 14492 QYFDD SLGGPV SGYSV VDY ADI- 54 VH4-34 VL3-21 AKASS QVWDD 4 25 22 14493 GSYHFE ADDHAV YWFDP ADI- 55 VH3-30 VL2-8 ARDQW SSYAGS 18 8 5 14494 LVPDY NSV ADI- 56 VH2-5 VK1-39 VHSDL QQSYTF 65 12 14 14495 YDRGG PYT YYLFYF DY ADI- 57 VH5-51 VK1-33 GRQEL QHYDN 59 17 9 14496 QGSFTI LLLFT ADI- 58 VH2-5 VK1-39 VHSDL QQVYT 65 13 15 14497 YDSGG SPYT YYLYY FDY ADI- 59 VH2-5 VK1-39 VHSDL QQSYSI 65 11 7 14498 YDRNA PYT YYLHY FDF ADI- 60 VH2-5 VK1-39 VHSDL QQSYTS 65 19 11 14499 YDSSG PYT YYLYY FDY ADI- 61 VH3-15 VL1-47 TTGPPY AAWDD 60 13 2 14500 KYSDST RLSGPV GYSVV DY ADI- 62 VH1-69 VK3-15 ATAGW QQYNN 54 34 4 14501 FGELVR WPPLT FDS ADI- 63 VH1-69 VK1-12 ARVAG QQAKS 49 14 15 14502 LGNSY FPYT GRYFDV ADI- 64 VH3-21 VL3-21 AREGS QVWDS 27 21 9 14503 DTEYW GDHPWL RLTPPM DV ADI- 65 VH3-48 VK3-15 ARDLS QQYDR 14 8 3 14504 GSPAYS WPPWT GSWV ADI- 66 VH1-2 VK4-1 ASEPPG QQYFSI 53 13 8 14505 VGFGLI PPT PHYYF DN ADI- 67 VH1-69 VK3-15 ARPAG QEYND 37 30 11 14506 DFGDL WPPQLS KWVRS PFDY ADI- 68 VH2-5 VK1-39 VHSDV QQSYSS 65 11 12 14507 YTTGG PYT YYLYY FDY ADI- 69 VH1-18 VK2-30 ARDSG MQATH 19 41 8 14508 ATAAGI WPRT LWDY ADI- 70 VH1-18 VK2-30 ARDVP MEGSH 22 26 11 14509 ADGVH WAPT FMDV ADI- 71 VH1-69 VK3-20 AIIDPQ QQYGT 3 39 17 14510 DCTSAS SPIT CFWVN WLDP ADI- 72 VH1-69 VK3-15 ARPAG QQYND 37 22 6 14511 DFGDL WPPQLT KWLRS PFDY ADI- 73 VH1-69 VK3-15 ARPER QQYND 39 22 5 14512 DFGHL WPPQLT KWLRS PFDY ADI- 74 VH1-69 VK3-20 AIIDPQ QQYGS 3 37 15 14513 DCTRA APIT SCFWV NWLAP ADI- 75 VH1-18 VK2-30 ARDVP MEGSH 22 22 10 14514 GDGVH WAPT FMDV ADI- 76 VH3-30 VK3-15 ARNTIF QQYNN 36 16 6 14515 GVVDY WPPWT ADI- 77 VH1-18 VK2-30 ARDKG MESTH 12 16 2 14516 VTVAG WPPYT SLLDY ADI- 78 VH1-18 VK2-30 ARDSPS MQATH 21 38 4 14518 DTAAA WPRLS LLDF ADI- 79 VH1-24 VK1-39 ATVIAV QQSYII 58 31 13 14519 GAYDI PYT ADI- 80 VH4-34 VL3-21 ARASS QVWDD 8 15 10 14520 GSYNFE PSDHAV YWFDP ADI- 81 VH1-18 VK2-30 ARDPPS MQATD 16 16 5 14521 LTAAG WPRT TLDY ADI- 82 VH1-2 VK3-15 ARDLY HQYND 15 26 10 14522 SSGWL WPYT DN ADI- 83 VH3-15 VL1-47 STGPPY AAWDD 60 18 14 14523 SYFDSS SLSGPV GYSVV DY ADI- 84 VH3-48 VK3-20 VRSLH QQSGSS 69 14 8 14524 WGAAI PYT ERWDV ADI- 85 VH3-30 VL2-8 ARDQW SSYAGS 18 9 5 14525 LVPDY NSV ADI- 86 VH4- VL3-25 ARGRG QSSDSS 30 33 11 14526 304 YSYGW GNYVV RYFDS ADI- 87 VH1-69 VK3-20 AIIDPQ QQYGS 3 46 11 14527 DCTAA SPIT SCFWV NWLDP ADI- 88 VH1-69 VK3-15 ARPAG QEYND 37 29 8 14528 DFGDL WPPQLT KWVRS PFDY ADI- 89 VH3-15 VL1-40 STGPPY AAWDD 60 18 22 14529 SYFDSS SLSGPV GYSVV DY ADI- 90 VH1-69 VK3-15 ARPEG QEYND 39 26 8 14530 DFGDL WPPQLT KWVRS PFDY ADI- 91 VH1-69 VK3-20 AIIDPQ QQYET 3 37 13 14531 DCTRA SPIT SCFWV NWLAP ADI- 92 VH3-15 VL1-47 STGPPY AAWDD 60 19 14 14532 SYFDSS SLSGPV GYSVV DY ADI- 93 VH1-69 VL1-36 ARDLQ AAWDD 13 26 10 14533 TGIMSS SLNGWV VRSEY RGFMDP ADI- 94 VH3-30 VL3-21 AKSSRL QVWDN 7 17 10 14534 LDWLY SNSQGV NMDF ADI- 95 VH4- VL3-25 ARGRG QSSDSS 30 32 9 14535 304 YTYGW GNVVL RYFDY ADI- 96 VH3-30 VK1-5 ARDSG QQYSS 20 17 11 14536 TLTGLP YSWT HDAFDI ADI- 97 VH3-15 VL1-47 STGPPY AAWDD 60 19 14 14537 SYFDSS SLSGPV GYSVV DY ADI- 98 VH3-30 VL3-21 AKSSRF QVWDN 7 18 14 14538 LDWLY SHSQGV NMDF ADI- 99 VH3-33 VK1-5 ARDSG HHYNS 20 23 10 14539 TLTGLP YSWT HDAFDV ADI- 100 VH3-30 VK4-1 ARDGD QQYSSP 11 13 5 14540 LVAVP PYT AAIGFDS ADI- 101 VH3-21 VL1-40 ARVIGD QSYDSS 50 26 4 14541 GTILGV LSVI VFDY ADI- 102 VH5-51 VL6-57 TIILIPA QSYDSS 61 10 6 14542 PIRAPD YHVV GFDI ADI- 103 VH1-69 VK1-12 ARVAG QQANS 49 14 7 14543 LGNSY FPYT GRYPDL ADI- 104 VH5-51 VL3-21 ARMLA QVWDS 35 14 5 14544 SVGLSN ISDHVL FDA ADI- 105 VH3-15 VK1-39 TSHAY QQCYS 64 9 8 14545 NSDWF APIT VTTDY YYYMDV ADI- 106 VH1-69 VK3-20 ARGISP HHYGT 29 22 11 14546 RTNSD SPHT WNHNY FYYYM DV ADI- 107 VH2-26 VK2-30 ARVLT MQGSH 51 24 11 14547 TWHGP WPHT DY ADI- 108 VH3-7 VL3-21 ARDVW QVWDS 25 11 6 14548 GWELV SRDHVV GWLDP ADI- 109 VH2-70 VK1-39 ARTPIY QQSYST 48 7 0 14549 DSSGY PVT YLYYF DS ADI- 110 VH3-30 VK4-1 ARDGDI QQYSSP 10 13 5 14550 VAVPA PYT AIGLDY ADI- 111 VH4-b VL3-25 ARGRG QSGDTS 30 37 9 14551 YSYGW GSYVV RFFDN ADI- 112 VH1-69 VK3-20 ARSRK QQYGR 45 30 13 14552 NVIGDT SMT SAWEH MYFYM DV ADI- 113 VH1-69 VK3-20 ARSNP QQYGA 43 17 16 14553 VARDF SAFS WSGYS DDSSY AMDV ADI- 114 VH3-15 VL1-47 TTGPPY AAWDD 60 7 4 14554 KYFDST RMSGPV GYSVV DY ADI- 115 VH3-23 VK3-11 AKAYC HQRSD 5 16 7 14555 SNKAC WPLT HGGYF DY ADI- 116 VH3-7 VK3-11 ARESGL QHRSD 28 12 7 14556 PRGAF WWT QI ADI- 117 VH4-34 VK3-20 ARGRK QQYGS 31 18 5 14557 LFEVPP SPQT KAPDY ADI- 118 VH3-23 VK3-11 AKAYC QQRST 5 14 6 14558 SDSCH WPLT GGYFDY ADI- 119 VH3-15 VL1-47 TTGPPY AAWDD 60 9 14 14559 QYYDS SLSGPV TGYSV VDY ADI- 120 VH5-51 VK3-11 ARQTT QQRSN 41 12 4 14560 MTPDA WGVGT FDL ADI- 121 VH1-69 VK3-20 ARSKR HHFGT 42 22 15 14561 LPAGLS TPWT TSDYY YYYLDV ADI- 122 VH1-69 VK1-12 ATVAG QQAKS 57 29 12 14562 LGTSY FPYT GRYLES ADI- 123 VH3-48 VK3-11 VRDSR QQRRN 66 21 2 14563 GPTTQ WPPLT WLTGY FDF

TABLE 3 Affinity and Neutralization data for anti-RSV antibodies Neut IC₅₀ Neut IC₅₀ Prefusion Postfusion Prefusion Postfusion (μg/ml) (μg/ml) Antibody subtype A subtype A subtype B subtype B subtype subtype Name number (Ab #) K_(D) (M)* K_(D) (M)* K_(D) (M)* K_(D) (M)* A* B* ADI- 1 4.35E−09 1.18E−08 8.92E−09 8.29E−09 0.289 0.237 14438 ADI- 2 2.28E−08 5.16E−09 2.25E−08 1.62E−08 >10 4.122 14439 ADI- 3 1.39E−08 1.45E−09 8.12E−09 2.39E−09 >10 4.180 14440 ADI- 4 8.59E−09 NB 8.06E−09 NB >10 3.920 14441 ADI- 5 4.73E−10 NB 7.28E−10 NB 0.002 0.015 14442 ADI- 6 1.77E−10 1.90E−10 2.05E−10 1.37E−10 0.047 0.063 14443 ADI- 7 NB NB 8.33E−08 NB >10 >10 14444 ADI- 8 3.41E−08 4.92E−09 3.58E−08 1.52E−08 >10 1.213 14445 ADI- 9 2.31E−10 2.13E−10 2.57E−10 1.37E−10 0.091 0.187 14446 ADI- 10 4.37E−10 3.39E−10 5.46E−10 2.71E−10 0.143 0.372 14447 ADI- 11 3.81E−10 NB 5.96E−10 NB 0.043 0.066 14448 ADI- 12 1.93E−10 2.04E−10 5.94E−10 4.62E−10 0.193 0.182 14449 ADI- 13 1.76E−10 2.27E−10 2.29E−10 1.42E−10 0.195 0.315 14450 ADI- 14 3.16E−10 NB 4.96E−10 NB 0.020 0.060 14451 ADI- 15 2.20E−10 2.17E−10 2.47E−10 1.39E−10 0.076 0.157 14452 ADI- 16 3.94E−10 2.61E−10 6.70E−10 2.28E−10 >10 >10 14453 ADI- 17 7.43E−10 2.97E−10 6.87E−10 4.83E−10 0.230 2.537 14454 ADI- 18 2.14E−09 NB 4.40E−09 NB 0.012 0.036 14455 ADI- 19 6.03E−09 NB 3.91E−09 NB >10 0.372 14456 ADI- 20 4.66E−10 3.80E−10 2.03E−09 4.61E−10 0.200 0.251 14457 ADI- 21 1.39E−10 1.96E−10 1.84E−10 1.26E−10 0.161 0.104 14458 ADI- 22 2.30E−10 2.64E−10 3.04E−10 1.83E−10 0.396 0.753 14459 ADI- 23 2.69E−10 2.86E−09 1.09E−09 2.56E−09 0.102 0.239 14460 ADI- 24 1.90E−10 2.31E−10 2.44E−10 1.56E−10 0.129 0.152 14461 ADI- 25 1.12E−08 NB 1.68E−08 NB 2.706 2.631 14462 ADI- 26 4.25E−10 NB 1.86E−09 NB 0.009 0.036 14463 ADI- 27 3.22E−09 NB 3.11E−09 NB >10 0.161 14464 ADI- 28 1.22E−09 NB 2.74E−09 NB 0.431 0.124 14465 ADI- 29 3.48E−10 2.47E−10 3.98E−10 1.69E−10 0.144 0.263 14466 ADI- 30 4.90E−10 NB 2.44E−09 NB 0.060 0.065 14467 ADI- 31 1.51E−09 2.97E−10 5.52E−10 2.41E−10 0.241 2.412 14468 ADI- 32 3.82E−10 3.01E−10 2.37E−09 2.90E−09 0.050 0.013 14469 ADI- 33 5.42E−10 3.58E−10 5.49E−10 3.14E−10 0.226 0.473 14470 ADI- 34 1.69E−10 2.12E−10 2.17E−10 1.50E−10 0.096 0.116 14471 ADI- 35 1.55E−09 2.24E−10 8.91E−10 1.51E−10 14473 ADI- 36 4.43E−10 NB 8.77E−10 NB 0.019 0.016 14474 ADI- 37 3.36E−10 2.99E−10 5.32E−10 2.42E−10 0.391 0.522 14475 ADI- 38 1.95E−09 8.27E−10 1.14E−08 9.12E−09 0.929 2.186 14476 ADI- 39 1.36E−09 3.61E−10 8.78E−10 1.22E−09 >10 >10 14477 ADI- 40 1.60E−09 NB 3.05E−09 NB 0.163 0.057 14478 ADI- 41 3.95E−08 NB NB NB 4.090 22.680 14479 ADI- 42 6.43E−09 NB 7.57E−09 NB >10 2.759 14480 ADI- 43 1.26E−10 NB 2.39E−10 NB 0.024 0.031 14482 ADI- 44 2.67E−10 NB 4.85E−10 2.00E−08 0.031 0.030 14483 ADI- 45 4.65E−10 3.89E−10 2.18E−09 3.94E−10 0.448 0.169 14484 ADI- 46 6.45E−09 1.52E−09 7.52E−09 6.42E−10 >10 2.813 14485 ADI- 47 2.61E−09 5.29E−10 1.78E−09 6.36E−10 14486 ADI- 48 8.04E−08 NB NB NB >10 >10 14487 ADI- 49 NB 1.48E−08 NB NB >10 >10 14488 ADI- 50 3.82E−10 NB 6.78E−10 NB 0.023 0.021 14489 ADI- 51 9.07E−09 NB 2.62E−08 NB 1.016 0.113 14490 ADI- 52 1.83E−10 2.38E−10 2.37E−10 1.58E−10 0.105 0.102 14491 ADI- 53 1.24E−10 1.66E−10 1.76E−10 1.11E−10 0.204 0.681 14492 ADI- 54 9.76E−10 NB 3.02E−09 NB 0.009 1.272 14493 ADI- 55 1.75E−10 2.40E−10 2.32E−10 1.55E−10 0.084 0.089 14494 ADI- 56 1.15E−09 3.67E−10 1.24E−09 1.71E−09 0.864 17.440 14495 ADI- 57 1.88E−10 NB 6.71E−09 NB 0.006 >10 14496 ADI- 58 3.49E−10 3.58E−10 4.57E−09 4.82E−09 0.115 0.116 14497 ADI- 59 5.67E−10 4.12E−10 1.05E−09 2.27E−09 >10 >10 14498 ADI- 60 1.71E−09 4.15E−10 3.80E−09 2.99E−09 >10 >10 14499 ADI- 61 6.38E−10 7.14E−10 9.10E−10 1.27E−10 0.415 0.552 14500 ADI- 62 1.59E−08 NB 3.47E−08 NB 12.350 2.288 14501 ADI- 63 5.00E−09 NB 1.10E−08 NB >10 2.718 14502 ADI- 64 1.12E−10 2.61E−08 7.76E−10 0.016 0.026 14503 ADI- 65 4.54E−09 5.83E−10 1.12E−09 5.20E−10 2.810 13.390 14504 ADI- 66 1.56E−10 NB 2.90E−10 NB 0.065 0.018 14505 ADI- 67 5.91E−08 1.31E−08 5.02E−08 2.45E−08 >10 6.250 14506 ADI- 68 3.13E−10 2.66E−10 4.69E−10 4.13E−10 0.319 0.173 14507 ADI- 69 3.27E−10 NB 5.77E−10 NB 0.029 0.057 14508 ADI- 70 3.64E−10 NB 6.15E−10 NB 0.011 0.016 14509 ADI- 71 4.13E−09 7.83E−10 1.96E−09 6.19E−10 >10 >10 14510 ADI- 72 4.14E−09 9.88E−10 2.60E−09 1.25E−09 >10 7.037 14511 ADI- 73 1.67E−08 2.67E−09 2.13E−09 5.87E−10 >10 >10 14512 ADI- 74 3.86E−09 1.21E−09 4.42E−09 9.62E−10 4.807 2.201 14513 ADI- 75 3.83E−10 NB 6.82E−10 NB 0.046 0.074 14514 ADI- 76 5.21E−10 NB 1.10E−09 NB 0.051 0.049 14515 ADI- 77 3.36E−10 NB 6.02E−10 NB 0.018 0.047 14516 ADI- 78 2.83E−10 NB 4.97E−10 NB 0.019 0.032 14518 ADI- 79 3.76E−09 NB 3.85E−09 NB 12.230 3.426 14519 ADI- 80 1.26E−10 NB 2.40E−10 NB 0.029 0.045 14520 ADI- 81 4.61E−10 NB 9.27E−10 NB 0.083 0.123 14521 ADI- 82 NB 1.49E−09 NB 1.06E−09 3.528 7.285 14522 ADI- 83 1.36E−10 1.92E−10 1.98E−10 1.31E−10 0.239 0.151 14523 ADI- 84 NB 8.26E−10 NB 7.71E−10 6.046 6.000 14524 ADI- 85 1.79E−10 2.30E−10 2.32E−10 1.49E−10 0.135 0.108 14525 ADI- 86 2.57E−09 3.46E−10 1.67E−09 3.42E−10 2.361 9.672 14526 ADI- 87 4.65E−09 8.89E−10 2.84E−09 6.45E−10 >10 >10 14527 ADI- 88 1.60E−07 3.52E−08 9.07E−08 >10 0.705 14528 ADI- 89 1.16E−09 1.71E−09 1.21E−09 7.98E−10 2.382 0.991 14529 ADI- 90 1.90E−07 4.72E−08 8.83E−08 3.76E−08 >10 >10 14530 ADI- 91 6.64E−08 1.26E−08 5.37E−08 2.38E−08 >10 >10 14531 ADI- 92 1.48E−10 2.24E−10 2.10E−10 1.36E−10 0.168 0.208 14532 ADI- 93 5.38E−09 NB 2.31E−09 NB >10 0.442 14533 ADI- 94 1.63E−08 1.00E−09 5.05E−09 9.30E−10 >10 >10 14534 ADI- 95 3.21E−09 2.30E−10 1.81E−09 2.38E−10 >10 >10 14535 ADI- 96 6.20E−10 4.04E−10 8.49E−10 3.82E−10 0.560 0.696 14536 ADI- 97 3.00E−10 2.11E−10 2.93E−10 1.42E−10 0.272 0.292 14537 ADI- 98 4.41E−09 3.50E−10 2.12E−09 1.54E−10 >10 >10 14538 ADI- 99 2.16E−09 7.38E−10 5.09E−09 5.71E−09 0.727 0.302 14539 ADI- 100 9.23E−09 NB 2.31E−09 NB >10 >10 14540 ADI- 101 3.23E−10 NB 5.32E−10 NB 0.023 0.106 14541 ADI- 102 2.78E−09 NB 2.64E−08 NB 0.008 4.299 14542 ADI- 103 NB NB NB NB >10 >10 14543 ADI- 104 4.28E−10 NB 2.24E−08 NB >10 >10 14544 ADI- 105 1.43E−09 NB 3.63E−09 NB 0.036 0.073 14545 ADI- 106 3.74E−09 5.89E−10 1.83E−09 4.72E−10 >10 >10 14546 ADI- 107 2.11E−10 1.69E−10 2.82E−10 2.69E−10 0.198 0.252 14547 ADI- 108 3.31E−10 NB 5.02E−10 NB 0.034 0.094 14548 ADI- 109 2.70E−09 3.26E−10 3.29E−09 2.49E−09 >10 >10 14549 ADI- 110 1.04E−08 NB 3.60E−09 NB 2.615 >10 14550 ADI- 111 1.56E−09 2.07E−10 1.15E−09 1.95E−10 14551 ADI- 112 9.99E−09 1.27E−09 3.62E−09 1.11E−09 >10 >10 14552 ADI- 113 NB 6.71E−08 NB 1.17E−07 >10 >10 14553 ADI- 114 3.88E−10 3.90E−10 1.97E−10 0.736 0.787 14554 ADI- 115 NB NB 1.58E−08 NB >10 >10 14555 ADI- 116 NB NB NB >10 >10 14556 ADI- 117 3.14E−08 NB NB NB >10 >10 14557 ADI- 118 NB NB 2.91E−08 NB >10 >10 14558 ADI- 119 5.38E−10 2.04E−10 3.69E−10 1.29E−10 0.057 0.031 14559 ADI- 120 NB 8.74E−10 1.14E−08 3.29E−10 >10 >10 14560 ADI- 121 1.50E−08 3.09E−09 7.94E−09 2.28E−09 >10 >10 14561 ADI- 122 4.53E−09 NB 1.39E−08 NB >10 10.470 14562 ADI- 123 NB NB NB >10 >10 14563 *NN; non-neutralizing, NB; non-binding, ND; not determined. IgG KDs were calculated for antibodies with BLI binding responses >0.1 nm. Antibodies with BLI binding responses <0.05 nm were designated as NB.

TABLE 4 Bin, patch, and antigenic site assignments for anti-RSV antibodies Antibody Antigenic number Rin Patch Site Name (Ab #) Assignment Assignment Assignment ADI-14438 1 Mota ADI-14439 2 Unknown ADI-14440 3 Unknown ADI-14441 4 MPE8 ADI-14442 5 Mota/MPE8 4, 2 V ADI-14443 6 14443 9 IV ADI-14444 7 D25 ADI-14445 8 Unknown ADI-14446 9 14443 9 IV ADI-14447 10 Mota 5 II ADI-14448 11 Mota/MPE8 III ADI-14449 12 14443 9 IV ADI-14450 13 14443 9 IV ADI-14451 14 MPE8 4 V ADI-14452 15 14443 9 IV ADI-14453 16 14469 8 I ADI-14454 17 14469 8 I ADI-14455 18 D25/mota/MPE8 ADI-14456 19 101F ADI-14457 20 14469 8 I ADI-14458 21 14443 9 IV ADI-14459 22 14443 9 IV ADI-14460 23 14443 9 IV ADI-14461 24 14443 9 IV ADI-14462 25 101F ADI-14463 26 D25/mota/MPE8 4 V ADI-14464 27 101F ADI-14465 28 101F 9 IV ADI-14466 29 Mota 5 II ADI-14467 30 D25/mota/MPE8 4, 2 V ADI-14468 31 14469 I ADI-14469 32 14469 8 I ADI-14470 33 14469 I ADI-14471 34 14443 9 IV ADI-14473 35 Mota 5 II ADI-14474 36 D25/mota/MPE8 4, 2 V ADI-14475 37 14469 8 I ADI-14476 38 13390 I ADI-14477 39 13390 8 I ADI-14478 40 Mota/MPE8 III ADI-14479 41 Mota ADI-14480 42 MPE8 ADI-14482 43 14443 9 IV ADI-14483 44 Mota/MPE8 III ADI-14484 45 14469 8 I ADI-14485 46 Unknown ADI-14486 47 101F ADI-14487 48 Mota ADI-14488 49 Unknown ADI-14489 50 Mota/MPE8 4, 2 V ADI-14490 51 D25/mota/MPE8 ADI-14491 52 14443 9 IV ADI-14492 53 14443 9 IV ADI-14493 54 14443 9 IV ADI-14494 55 14443 9 IV ADI-14495 56 Unknown I ADI-14496 57 D25 1 Ø ADI-14497 58 14469 8 I ADI-14498 59 14469 8 I ADI-14499 60 13390 8 I ADI-14500 61 14443 9 IV ADI-14501 62 MPE8 ADI-14502 63 AM14 ADI-14503 64 14443 9 IV ADI-14504 65 Mota ADI-14505 66 14443 9 IV ADI-14506 67 Unknown ADI-14507 68 14469 I ADI-14508 69 MPE8 4 V ADI-14509 70 Mota/MPE8 4 V ADI-14510 71 Unknown ADI-14511 72 Unknown ADI-14512 73 Unknown ADI-14513 74 Unknown ADI-14514 75 Mota/MPE8 4 V ADI-14515 76 Mota/MPE8 V ADI-14516 77 D25/mota/MPE8 4 V ADI-14518 78 Mota/MPE8 4 V ADI-14519 79 101F ADI-14520 80 14443 9 IV ADI-14521 81 D25/mota/MPE8 4 V ADI-14522 82 Unknown ADI-14523 83 14443 9 IV ADI-14524 84 Unknown ADI-14525 85 14443 9 IV ADI-14526 86 Unknown ADI-14527 87 Unknown ADI-14528 88 Unknown ADI-14529 89 101F 9 IV ADI-14530 90 Unknown ADI-14531 91 Unknown ADI-14532 92 14443 9 IV ADI-14533 93 Unknown ADI-14534 94 Unknown ADI-14535 95 Unknown ADI-14536 96 Mota 5 II ADI-14537 97 14443 9 IV ADI-14538 98 Mota ADI-14539 99 Mota ADI-14540 100 Unknown ADI-14541 101 MPE8 III ADI-14542 102 D25 ADI-14543 103 Unknown ADI-14544 104 D25 1 Ø ADI-14545 105 D25 1, 2 Ø ADI-14546 106 Unknown ADI-14547 107 14443 9 IV ADI-14548 108 14443 9 IV ADI-14549 109 13390 ADI-14550 110 Unknown ADI-14551 111 Unknown 1 UK ADI-14552 112 Unknown ADI-14553 113 Unknown ADI-14554 114 14443 ADI-14555 115 Unknown ADI-14556 116 Unknown ADI-14557 117 101F ADI-14558 118 Unknown ADI-14559 119 14443 9 IV ADI-14560 120 Mota ADI-14561 121 Unknown ADI-14562 122 AM14 ADI-14563 123 Unknown

TABLE 5 A subset of anti-RSV F antibodies cross-neutralize human metapneumovirus. Antibody Prefusion Postfusion number HMPV-A1 RSV-A2 IC₅₀ RSV F K_(D) RSV F K_(D) RSV F Name (Ab #) IC₅₀ (μg/ml) (μg/ml) (M) (M) Binding Site ADI- 11 0.05 0.04 3.8 × 10⁻¹⁰ N.B. III 14448 ADI- 4 37.8 >25 8.6 × 10⁻⁹ N.B. III* 14441 ADI- 62 31.4 12.4 1.6 × 10⁻⁸ N.B. III* 14501 MPE8 N/A 0.07 0.04 — — — Control N.B., non-binder; N/A, not applicable *Binding site assignment based on competition only.

Materials and Methods Study Design

To profile the antibody response to RSV F, peripheral blood mononuclear cells were obtained from an adult donor approximately between 20-35 years of age, and monoclonal antibodies from RSV F-reactive B cells were isolated therefrom. The antibodies were characterized by sequencing, binding, epitope mapping, and neutralization assays. All samples for this study were collected with informed consent of volunteers. This study was unblinded and not randomized. At least two independent experiments were performed for each assay.

Generation of RSV F Sorting Probes

The soluble prefusion and postfusion probes were based on the RSV F ΔFP and DS-Cav1 constructs that we previously crystallized and determined to be in the pre- and postfusion conformations, respectively (11, 15). To increase the avidity of the probes and to uniformly orient the RSV F proteins, the trimeric RSV F proteins were coupled to tetrameric streptavidin through biotinylation of a C-terminal AviTag. For each probe, both a C-terminal His-Avi tagged version and a C-terminal StrepTagII version were co-transfected into FreeStyle 293-F cells. The secreted proteins were purified first over Ni-NTA resin to remove trimers lacking the His-Avi tag. The elution from the Ni-NTA purification was then purified over Strep-Tactin resin. Due to the low avidity of a single StrepTagII for the Strep-Tactin resin, additional washing steps were able to remove singly StrepTagged trimers. This resulted in the purification of trimers containing two StrepTagII tagged monomers and therefore only one His-Avi tagged monomer. This purification scheme results in a single AviTag per trimer which greatly reduces the aggregation or ‘daisy-chaining’ that occurs when trimeric proteins containing three AviTags are incubated with tetrameric streptavidin. RSV F trimers were biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromatography on a Superdex 200 column (GE Healthcare). Quantification of the number of biotin moieties per RSV F trimer was performed using the Quant*Tag Biotin Kit per the manufacturer's instructions (Vector Laboratories).

Single B-Cell Sorting

Peripheral blood mononuclear cells were stained using anti-human IgG (BV605), IgA (FITC), CD27 (BV421), CD8 (PerCP-Cy5.5), CD14 (PerCP-Cy5.5), CD19 (PECy7), CD20 (PECy7) and a mixture of dual-labeled DS-Cav1 and F ΔFP tetramers (50 nM each). Dual-labeled RSV F tetramers were generated by incubating the individual AviTagged RSV F proteins with premium-grade phycoerythrin-labeled streptavidin (Molecular Probes) or premium-grade allophycocyanin-labeled streptavidin for at least 20 minutes on ice at a molar ratio of 4:1. Tetramers were prepared fresh for each experiment. Single cells were sorted on a BD fluorescence-activated cell sorter Aria II into 96-well PCR plates (BioRad) containing 20 μL/well of lysis buffer [5 μL of 5× first strand cDNA buffer (Invitrogen), 0.25 μL RNaseOUT (Invitrogen), 1.25 μL dithiothreitol (Invitrogen), 0.625 μL NP-40 (New England Biolabs), and 12.6 μL dH₂O]. Plates were immediately frozen on dry ice before storage at −80° C.

Amplification and Cloning of Antibody Variable Genes

Single B cell PCR was performed as described previously (22). Briefly, IgH, Igλ and Igκ variable genes were amplified by RT-PCR and nested PCR reactions using cocktails of IgG and IgA-specific primers (22). The primers used in the second round of PCR contained 40 base pairs of 5′ and 3′ homology to the cut expression vectors to allow for cloning by homologous recombination into Saccharomyces cerevisiae (40). PCR products were cloned into S. cerevisiae using the lithium acetate method for chemical transformation (41). Each transformation reaction contained 20 μL of unpurified heavy chain and light chain PCR product and 200 ng of cut heavy and light chain plasmids. Following transformation, individual yeast colonies were picked for sequencing and characterization.

Expression and Purification of IgGs and Fab Fragments

Anti-RSV F IgGs were expressed in S. cerevisiae cultures grown in 24-well plates, as described previously (23). Fab fragments used for competition assays were generated by digesting the IgGs with papain for 2 hours at 30° C. The digestion was terminated by the addition of iodoacetamide, and the Fab and Fc mixtures were passed over Protein A agarose to remove Fc fragments and undigested IgG. The flowthrough of the Protein A resin was then passed over CaptureSelect™ IgG-CH1 affinity resin (ThermoFischer Scientific), and eluted with 200 mM acetic acid/50 mM NaCl pH 3.5 into ⅛th volume 2M Hepes pH 8.0. Fab fragments then were buffer-exchanged into PBS pH 7.0.

Biolayer Interferometry Binding Analysis

IgG binding to DS-Cav1 and FΔ FP was determined by BLI measurements using a ForteBio Octet HTX instrument (Pall Life Sciences). For high-throughput K_(D) screening, IgGs were immobilized on AHQ sensors (Pall Life Sciences) and exposed to 100 nM antigen in PBS containing 0.1% BSA (PBSF) for an association step, followed by a dissociation step in PBSF buffer. Data was analyzed using the ForteBio Data Analysis Software 7. The data was fit to a 1:1 binding model to calculate an association and dissociation rate, and K_(D) was calculated using the ratio k_(d)/k_(a).

Antibody Competition Assays

Antibody competition assays were performed as previously described (23). Antibody competition was measured by the ability of a control anti-RSV F Fab to inhibit binding of yeast surface-expressed anti-RSV F IgGs to either DS-Cav1 or FΔ FP. 50 nM biotinylated DS-Cav1 or FΔ FP was pre-incubated with 1 μM competitor Fab for 30 min at room temperature and then added to a suspension of yeast expressing anti-RSV F IgG. Unbound antigen was removed by washing with PBS containing 0.1% BSA (PB SF). After washing, bound antigen was detected using streptavidin Alexa Fluor 633 at a 1:500 dilution (Life Technologies) and analyzed by flow cytometry using a FACSCanto II (BD Biosciences). The level of competition was assessed by measuring the fold reduction in antigen binding in the presence of competitor Fab relative to an antigen-only control. Antibodies were considered competitors when a greater than five-fold reduction was observed in the presence of control Fab relative to an antigen-only control.

Expression, Purification and Biotinylation of preF Patch Variants

A panel of 9 patches of 2-4 mutations uniformly covering the surface of the preF molecule was designed based on the structure of prefusion RSV F (10). For known antigenic sites, including those recognized by motavizumab, 101F, D25, AM14 and MPE8, patches incorporated residues associated with viral escape or known to be critical for antibody binding. Residues with high conservation across 184 subtype A, subtype B and bovine RSV F sequences were avoided where possible to minimize the likelihood of disrupting protein structure. The mutations present in each patch variant are shown in FIG. 7A. Mutations for each patch variant were cloned into the prefusion stabilized RSV F (DS-Cav1) construct with a C-terminal AviTag for site specific biotinylation. Proteins were secreted from FreeStyle 293-F cells, purified over Ni-NTA resin and biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromatography on a Superdex 200 column (GE Healthcare). A deglycosylated version of DS-Cav1 was produced by expressing DS-Cav1 in the presence of 1 μM kifunensine and digesting with 10% (wt/wt) EndoH before biotinylation.

Luminex Assay for Patch Variant Binding

Binding of isolated antibodies to the patch variants was determined using a high-throughput Luminex assay. Each biotinylated variant and a DS-Cav1 control were coupled to avidin coated MagPlex beads (Bio-Rad), each with a bead identification number reflecting a unique ratio of red and infrared dyes embedded within the bead. The coupled beads were then mixed with a six-fold serial dilution of each antibody, ranging from 400 nM to 1.4 pM, in a 384-well plate. Beads were washed using a magnetic microplate washer (BioTek) before incubation with a PE conjugated mouse anti-human IgG Fc secondary antibody (Southern Biotech). Beads were classified and binding of PE was measured using a FLEXMAP 3D flow cytometer (Luminex).

RSV Neutralization Assays

Viral stocks were prepared and maintained as previously described (61). Recombinant mKate-RSV expressing prototypic subtype A (strain A2) and subtype B (18537) F genes and the Katushka fluorescent protein were constructed as reported by Hotard et al. (62). HEp-2 cells were maintained in Eagle's minimal essential medium containing 10% fetal bovine serum supplemented with glutamine, penicillin and streptomycin. Antibody neutralization was measured by a fluorescence plate reader neutralization assay (15). A 30 μL solution of culture media containing 2.4×10⁴ HEp-2 cells was seeded in 384-well black optical bottom plate (Nunc, Thermo Scientific). IgG samples were serially diluted four-fold from 1:10 to 1:163840 and an equal volume of recombinant mKate-RSV A2 was added. Samples were mixed and incubated at 37° C. for one hour. After incubation, 50 μL mixture of sample and virus was added to cells in 384-well plate, and incubated at 37° C. for 22-24 hours. The assay plate was then measured for fluorescence intensity in a microplate reader at Ex 588 nm and Em 635 nm (SpectraMax Paradigm, molecular devices). IC₅₀ of neutralization for each sample was calculated by curve fitting using Prism (GraphPad Software Inc.).

Human Metapneumovirus Neutralization Assays

Predetermined amounts of GFP-expressing hMPV recombinant virus (NL/1/00, A1 sublineage, a kind gift of Bernadette van den Hoogen and Ron Fouchier, Rotterdam, the Netherlands) were mixed with serial dilutions of monoclonal antibodies before being added to cultures of Vero-118 cells growing in 96-well plates with Dulbecco's Modified Eagle's medium supplemented with 10% fetal calf serum. Thirty-six hours later, the medium was removed, PBS was added and the amount of GFP per well was measured with a Tecan microplate reader M200. Fluorescence values were represented as percent of a virus control without antibody.

Polyreactivity Assay

Antibody polyreactivity was assessed using a previously described high-throughput assay that measures binding to solubilized CHO cell membrane preparations (SMPs) (43). Briefly, two million IgG-presenting yeast were transferred into a 96-well assay plate and pelleted to remove the supernatant. The pellet was resuspended in 50 μL of 1:10 diluted stock b-SMPs and incubated on ice for 20 minutes. Cells were then washed twice with ice-cold PBSF and the cell pellet was re-suspended in 50 μL of secondary labeling mix (Extravidin-R-PE, anti-human LCFITC, and propidium iodide). The mix was incubated on ice for 20 minutes followed by two washes with ice-cold PBSF. Cells were then re-suspended in 100 μL of ice-cold PB SF, and the plate was run on a FACSCanto II (BD Biosciences) using a HTS sample injector. Flow cytometry data was analyzed for mean fluorescence intensity in the R-PE channel and normalized to proper controls in order to assess non-specific binding.

REFERENCES AND NOTES

-   1. A. L. Rogovik, B. Carleton, A. Solimano, R. D. Goldman,     Palivizumab for the prevention of respiratory syncytial virus     infection. Can Fam Physician 56, 769-772 (2010). -   2. B. S. Graham, Biological challenges and technological     opportunities for respiratory syncytial virus vaccine development.     Immunol Rev 239, 149-166 (2011). -   3. J. R. Groothuis, E. A. Simoes, V. G. Hemming, Respiratory     syncytial virus (RSV) infection in preterm infants and the     protective effects of RSV immune globulin (RSVIG). Respiratory     Syncytial Virus Immune Globulin Study Group. Pediatrics 95, 463-467     (1995). -   4. M. Magro, V. Mas, K. Chappell, M. Vazquez, O. Cano, D.     Luque, M. C. Terron, J. A. Melero, C. Palomo, Neutralizing     antibodies against the preactive form of respiratory syncytial virus     fusion protein offer unique possibilities for clinical intervention.     Proc Natl Acad Sci USA 109, 3089-3094 (2012). -   5. S. Johnson, C. Oliver, G. A. Prince, V. G. Hemming, D. S.     Pfarr, S. C. Wang, M. Dormitzer, J. O'Grady, S. Koenig, J. K.     Tamura, R. Woods, G. Bansal, D. Couchenour, E. Tsao, W. C.     Hall, J. F. Young, Development of a humanized monoclonal antibody     (MEDI-493) with potent in vitro and in vivo activity against     respiratory syncytial virus. J Infect Dis 176, 1215-1224 (1997). -   6. J. A. Beeler, K. van Wyke Coelingh, Neutralization epitopes of     the F glycoprotein of respiratory syncytial virus: effect of     mutation upon fusion function. J Virol 63, 2941-2950 (1989). -   7. R. A. Karron, D. A. Buonagurio, A. F. Georgiu, S. S.     Whitehead, J. E. Adamus, M. L. Clements-Mann, D. O. Harris, V. B.     Randolph, S. A. Udem, B. R. Murphy, M. S. Sidhu, Respiratory     syncytial virus (RSV) SH and G proteins are not essential for viral     replication in vitro: clinical evaluation and molecular     characterization of a cold-passaged, attenuated RSV subgroup B     mutant. Proc Natl Acad Sci USA 94, 13961-13966 (1997). -   8. J. O. Ngwuta, M. Chen, K. Modjarrad, M. G. Joyce, M. Kanekiyo, A.     Kumar, H. M. Yassine, S. M. Moin, A. M. Killikelly, G. Y. Chuang, A.     Druz, I. S. Georgiev, E. J. Rundlet, M. Sastry, G. B.     Stewart-Jones, Y. Yang, B. Zhang, M. C. Nason, C. Capella, M. E.     Peeples, J. E. Ledgerwood, J. S. McLellan, P. D. Kwong, B. S.     Graham, Prefusion F-specific antibodies determine the magnitude of     RSV neutralizing activity in human sera. Sci Transl Med 7, 309ra162     (2015). -   9. T. I.-R. S. Group, Palivizumab, a humanized respiratory syncytial     virus monoclonal antibody, reduces hospitalization from respiratory     syncytial virus infection in high-risk infants. Pediatrics 102,     531-537 (1998). -   10. J. S. McLellan, M. Chen, S. Leung, K. W. Graepel, X. Du, Y.     Yang, T. Zhou, U. Baxa, E. Yasuda, T. Beaumont, A. Kumar, K.     Modjarrad, Z. Zheng, M. Zhao, N. Xia, P. D. Kwong, B. S. Graham,     Structure of RSV fusion glycoprotein trimer bound to a     prefusion-specific neutralizing antibody. Science 340, 1113-1117     (2013). -   11. J. S. McLellan, Y. Yang, B. S. Graham, P. D. Kwong, Structure of     respiratory syncytial virus fusion glycoprotein in the postfusion     conformation reveals preservation of neutralizing epitopes. J Virol     85, 7788-7796 (2011). -   12. K. A. Swanson, E. C. Settembre, C. A. Shaw, A. K. Dey, R.     Rappuoli, C. W. Mandl, P. R. Dormitzer, A. Carfi, Structural basis     for immunization with postfusion respiratory syncytial virus fusion     F glycoprotein (RSV F) to elicit high neutralizing antibody titers.     Proc Natl Acad Sci USA 108, 9619-9624 (2011). -   13. L. Liljeroos, M. A. Krzyzaniak, A. Helenius, S. J. Butcher,     Architecture of respiratory syncytial virus revealed by electron     cryotomography. Proc Natl Acad Sci USA 110, 11133-11138 (2013). -   14. A. Krarup, D. Truan, P. Furmanova-Hollenstein, L. Bogaert, P.     Bouchier, I. J. Bisschop, M. N. Widjojoatmodjo, R. Zahn, H.     Schuitemaker, J. S. McLellan, J. P. Langedijk, A highly stable     prefusion RSV F vaccine derived from structural analysis of the     fusion mechanism. Nat Commun 6, 8143 (2015). -   15. J. S. McLellan, M. Chen, M. G. Joyce, M. Sastry, G. B.     Stewart-Jones, Y. Yang, B. Zhang, L. Chen, S. Srivatsan, A.     Zheng, T. Zhou, K. W. Graepel, A. Kumar, S. Moin, J. C.     Boyington, G. Y. Chuang, C. Soto, U. Baxa, A. Q. Bakker, H.     Spits, T. Beaumont, Z. Zheng, N. Xia, S. Y. Ko, J. P. Todd, S.     Rao, B. S. Graham, P. D. Kwong, Structure-based design of a fusion     glycoprotein vaccine for respiratory syncytial virus. Science 342,     592-598 (2013). -   16. M. J. Kwakkenbos, S. A. Diehl, E. Yasuda, A. Q. Bakker, C. M.     van Geelen, M. V. Lukens, G. M. van Bleek, M. N.     Widjojoatmodjo, W. M. Bogers, H. Mei, A. Radbruch, F. A.     Scheeren, H. Spits, T. Beaumont, Generation of stable monoclonal     antibody-producing B cell receptor-positive human memory B cells by     genetic programming. Nat Med 16, 123-128 (2010). -   17. D. Corti, S. Bianchi, F. Vanzetta, A. Minola, L. Perez, G.     Agatic, B. Guarino, C. Silacci, J. Marcandalli, B. J. Marsland, A.     Piralla, E. Percivalle, F. Sallusto, F. Baldanti, A. Lanzavecchia,     Cross-neutralization of four paramyxoviruses by a human monoclonal     antibody. Nature 501, 439-443 (2013). -   18. M. Magro, D. Andreu, P. Gomez-Puertas, J. A. Melero, C. Palomo,     Neutralization of human respiratory syncytial virus infectivity by     antibodies and low-molecular-weight compounds targeted against the     fusion glycoprotein. J Virol 84, 7970-7982 (2010). -   19. G. Taylor, E. J. Stott, J. Furze, J. Ford, P. Sopp, Protective     epitopes on the fusion protein of respiratory syncytial virus     recognized by murine and bovine monoclonal antibodies. J Gen Virol     73 (Pt 9), 2217-2223 (1992). -   20. L. J. Calder, L. Gonzalez-Reyes, B. Garcia-Barreno, S. A.     Wharton, J. J. Skehel, D. C. Wiley, J. A. Melero, Electron     microscopy of the human respiratory syncytial virus fusion protein     and complexes that it forms with monoclonal antibodies. Virology     271, 122-131 (2000). -   21. M. S. Gilman, S. M. Moin, V. Mas, M. Chen, N. K. Patel, K.     Kramer, Q. Zhu, S. C. Kabeche, A. Kumar, C. Palomo, T. Beaumont, U.     Baxa, N. D. Ulbrandt, J. A. Melero, B. S. Graham, J. S. McLellan,     Characterization of a Prefusion-Specific Antibody That Recognizes a     Quaternary, Cleavage-Dependent Epitope on the RSV Fusion     Glycoprotein. PLoS Pathog 11, e1005035 (2015). -   22. M. G. Joyce, A. K. Wheatley, P. V. Thomas, G. Y. Chuang, C.     Soto, R. T. Bailer, A. Druz, I. S. Georgiev, R. A. Gillespie, M.     Kanekiyo, W. P. Kong, K. Leung, S. N. Narpala, M. S.     Prabhakaran, E. S. Yang, B. Zhang, Y. Zhang, M. Asokan, J. C.     Boyington, T. Bylund, S. Darko, C. R. Lees, A. Ransier, C. H.     Shen, L. Wang, J. R. Whittle, X. Wu, H. M. Yassine, C. Santos, Y.     Matsuoka, Y. Tsybovsky, U. Baxa, J. C. Mullikin, K. Subbarao, D. C.     Douek, B. S. Graham, R. A. Koup, J. E. Ledgerwood, M. Roederer, L.     Shapiro, P. D. Kwong, J. R. Mascola, A. B. McDermott,     Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2     Influenza A Viruses. Cell 166, 609-623 (2016). -   23. J. Truck, M. N. Ramasamy, J. D. Galson, R. Rance, J.     Parkhill, G. Lunter, A. J. Pollard, D. F. Kelly, Identification of     antigen-specific B cell receptor sequences using public repertoire     analysis. J Immunol 194, 252-261 (2015). -   24. P. Parameswaran, Y. Liu, K. M. Roskin, K. K. Jackson, V. P.     Dixit, J. Y. Lee, K. L. Artiles, S. Zompi, M. J. Vargas, B. B.     Simen, B. Hanczaruk, K. R. McGowan, M. A. Tariq, N. Pourmand, D.     Koller, A. Balmaseda, S. D. Boyd, E. Harris, A. Z. Fire, Convergent     antibody signatures in human dengue. Cell host & microbe 13, 691-700     (2013). -   25. K. J. Jackson, Y. Liu, K. M. Roskin, J. Glanville, R. A. Hoh, K.     Seo, E. L. Marshall, T. C. Gurley, M. A. Moody, B. F. Haynes, E. B.     Walter, H. X. Liao, R. A. Albrecht, A. Garcia-Sastre, J.     Chaparro-Riggers, A. Rajpal, J. Pons, B. B. Simen, B.     Hanczaruk, C. L. Dekker, J. Laserson, D. Koller, M. M. Davis, A. Z.     Fire, S. D. Boyd, Human responses to influenza vaccination show     seroconversion signatures and convergent antibody rearrangements.     Cell host & microbe 16, 105-114 (2014). -   26. F. W. Henderson, A. M. Collier, W. A. Clyde, Jr., F. W. Denny,     Respiratory-syncytial-virus infections, reinfections and immunity. A     prospective, longitudinal study in young children. The New England     journal of medicine 300, 530-534 (1979). -   27. M. A. Moody, B. F. Haynes, Antigen-specific B cell detection     reagents: use and quality control. Cytometry A 73, 1086-1092 (2008). -   28. M. S. Habibi, A. Jozwik, S. Makris, J. Dunning, A. Paras, J. P.     DeVincenzo, C. A. de Haan, J. Wrammert, P. J. Openshaw, C. Chiu, I.     Mechanisms of Severe Acute Influenza Consortium, Impaired     Antibody-mediated Protection and Defective IgA B-Cell Memory in     Experimental Infection of Adults with Respiratory Syncytial Virus.     Am J Respir Crit Care Med 191, 1040-1049 (2015). -   29. T. Tiller, E. Meffre, S. Yurasov, M. Tsuiji, M. C.     Nussenzweig, H. Wardemann, Efficient generation of monoclonal     antibodies from single human B cells by single cell RT-PCR and     expression vector cloning. J Immunol Methods 329, 112-124 (2008). -   30. Z. A. Bornholdt, H. L. Turner, C. D. Murin, W. Li, D. Sok, C. A.     Souders, A. E. Piper, A. Goff, J. D. Shamblin, S. E. Wollen, T. R.     Sprague, M. L. Fusco, K. B. Pommert, L. A. Cavacini, H. L. Smith, M.     Klempner, K. A. Reimann, E. Krauland, T. U. Gerngross, K. D.     Wittrup, E. O. Saphire, D. R. Burton, P. J. Glass, A. B. Ward, L. M.     Walker, Isolation of potent neutralizing antibodies from a survivor     of the 2014 Ebola virus outbreak. Science 351, 1078-1083 (2016). -   31. J. F. Scheid, H. Mouquet, N. Feldhahn, M. S. Seaman, K.     Velinzon, J. Pietzsch, R. G. Ott, R. M. Anthony, H. Zebroski, A.     Hurley, A. Phogat, B. Chakrabarti, Y. Li, M. Connors, F.     Pereyra, B. D. Walker, H. Wardemann, D. Ho, R. T. Wyatt, J. R.     Mascola, J. V. Ravetch, M. C. Nussenzweig, Broad diversity of     neutralizing antibodies isolated from memory B cells in HIV-infected     individuals. Nature 458, 636-640 (2009). -   32. J. Wrammert, K. Smith, J. Miller, W. A. Langley, K. Kokko, C.     Larsen, N. Y. Zheng, I. Mays, L. Garman, C. Helms, J. James, G. M.     Air, J. D. Capra, R. Ahmed, P. C. Wilson, Rapid cloning of     high-affinity human monoclonal antibodies against influenza virus.     Nature 453, 667-671 (2008). -   33. S. D. Boyd, B. A. Gaeta, K. J. Jackson, A. Z. Fire, E. L.     Marshall, J. D. Merker, J. M. Maniar, L. N. Zhang, B. Sahaf, C. D.     Jones, B. B. Simen, B. Hanczaruk, K. D. Nguyen, K. C. Nadeau, M.     Egholm, D. B. Miklos, J. L. Zehnder, A. M. Collins, Individual     variation in the germline Ig gene repertoire inferred from variable     region gene rearrangements. J Immunol 184, 6986-6992 (2010). -   34. J. Sui, W. C. Hwang, S. Perez, G. Wei, D. Aird, L. M. Chen, E.     Santelli, B. Stec, G. Cadwell, M. Ali, H. Wan, A. Murakami, A.     Yammanuru, T. Han, N. J. Cox, L. A. Bankston, R. O. Donis, R. C.     Liddington, W. A. Marasco, Structural and functional bases for     broad-spectrum neutralization of avian and human influenza A     viruses. Nat Struct Mol Biol 16, 265-273 (2009). -   35. C. C. Huang, M. Venturi, S. Majeed, M. J. Moore, S.     Phogat, M. Y. Zhang, D. S. Dimitrov, W. A. Hendrickson, J.     Robinson, J. Sodroski, R. Wyatt, H. Choe, M. Farzan, P. D. Kwong,     Structural basis of tyrosine sulfation and VH-gene usage in     antibodies that recognize the HIV type 1 coreceptor-binding site on     gp120. Proc Natl Acad Sci USA 101, 2706-2711 (2004). -   36. C. H. Chan, K. G. Hadlock, S. K. Foung, S. Levy, V(H)1-69 gene     is preferentially used by hepatitis C virus-associated B cell     lymphomas and by normal B cells responding to the E2 viral antigen.     Blood 97, 1023-1026 (2001). -   37. E. E. Godoy-Lozano, J. Tellez-Sosa, G. Sanchez-Gonzalez, H.     Samano-Sanchez, A. Aguilar-Salgado, A. Salinas-Rodriguez, B.     Cortina-Ceballos, H. Vivanco-Cid, K. Hernandez-Flores, J. M.     Pfaff, K. M. Kahle, B. J. Doranz, R. E. Gomez-Barreto, H.     Valdovinos-Torres, I. Lopez-Martinez, M. H. Rodriguez, J.     Martinez-Barnetche, Lower IgG somatic hypermutation rates during     acute dengue virus infection is compatible with a germinal     center-independent B cell response. Genome Med 8, 23 (2016). -   38. J. Wrammert, D. Koutsonanos, G. M. Li, S. Edupuganti, J. Sui, M.     Morrissey, M. McCausland, I. Skountzou, M. Hornig, W. I. Lipkin, A.     Mehta, B. Razavi, C. Del Rio, N. Y. Zheng, J. H. Lee, M. Huang, Z.     Ali, K. Kaur, S. Andrews, R. R. Amara, Y. Wang, S. R. Das, C. D.     O'Donnell, J. W. Yewdell, K. Subbarao, W. A. Marasco, M. J.     Mulligan, R. Compans, R. Ahmed, P. C. Wilson, Broadly cross-reactive     antibodies dominate the human B cell response against 2009 pandemic     H1N1 influenza virus infection. J Exp Med 208, 181-193 (2011). -   39. S. F. Andrews, Y. Huang, K. Kaur, L. I. Popova, I. Y. Ho, N. T.     Pauli, C. J. Henry Dunand, W. M. Taylor, S. Lim, M. Huang, X.     Qu, J. H. Lee, M. Salgado-Ferrer, F. Krammer, P. Palese, J.     Wrammert, R. Ahmed, P. C. Wilson, Immune history profoundly affects     broadly protective B cell responses to influenza. Sci Transl Med 7,     316ra192 (2015). -   40. M. Liu, G. Yang, K. Wiehe, N. I. Nicely, N. A. Vandergrift, W.     Rountree, M. Bonsignori, S. M. Alam, J. Gao, B. F. Haynes, G.     Kelsoe, Polyreactivity and autoreactivity among HIV-1 antibodies. J     Virol 89, 784-798 (2015). -   41. H. Mouquet, J. F. Scheid, M. J. Zoller, M. Krogsgaard, R. G.     Ott, S. Shukair, M. N. Artyomov, J. Pietzsch, M. Connors, F.     Pereyra, B. D. Walker, D. D. Ho, P. C. Wilson, M. S. Seaman, H. N.     Eisen, A. K. Chakraborty, T. J. Hope, J. V. Ravetch, H.     Wardemann, M. C. Nussenzweig, Polyreactivity increases the apparent     affinity of anti-HIV antibodies by heteroligation. Nature 467,     591-595 (2010). -   42. R. L. Kelly, T. Sun, T. Jain, I. Caffry, Y. Yu, Y. Cao, H.     Lynaugh, M. Brown, M. Vasquez, K. D. Wittrup, Y. Xu, High throughput     cross-interaction measures for human IgG1 antibodies correlate with     clearance rates in mice. MAbs, 0 (2015). -   43. Y. Xu, W. Roach, T. Sun, T. Jain, B. Prinz, T. Y. Yu, J.     Torrey, J. Thomas, P. Bobrowicz, M. Vasquez, K. D. Wittrup, E.     Krauland, Addressing polyspecificity of antibodies selected from an     in vitro yeast presentation system: a FACS-based, high-throughput     selection and analytical tool. Protein Eng Des Sel 26, 663-670     (2013). -   44. D. R. Bowley, A. F. Labrijn, M. B. Zwick, D. R. Burton, Antigen     selection from an HIV-1 immune antibody library displayed on yeast     yields many novel antibodies compared to selection from the same     library displayed on phage. Protein Eng Des Sel 20, 81-90 (2007). -   45. H. Wu, D. S. Pfarr, S. Johnson, Y. A. Brewah, R. M. Woods, N. K.     Patel, W. I. White, J. F. Young, P. A. Kiener, Development of     motavizumab, an ultra-potent antibody for the prevention of     respiratory syncytial virus infection in the upper and lower     respiratory tract. Journal of molecular biology 368, 652-665 (2007). -   46. J. S. McLellan, M. Chen, J. S. Chang, Y. Yang, A. Kim, B. S.     Graham, P. D. Kwong, Structure of a major antigenic site on the     respiratory syncytial virus fusion glycoprotein in complex with     neutralizing antibody 101F. J Virol 84, 12236-12244 (2010). -   47. P. W. Parren, D. R. Burton, The antiviral activity of antibodies     in vitro and in vivo. Advances in immunology 77, 195-262 (2001). -   48. J. Foote, H. N. Eisen, Kinetic and affinity limits on antibodies     produced during immune responses. Proc Natl Acad Sci USA 92,     1254-1256 (1995). -   49. F. D. Batista, M. S. Neuberger, Affinity dependence of the B     cell response to antigen: a threshold, a ceiling, and the importance     of off-rate. Immunity 8, 751-759 (1998). -   50. J. E. Schuster, R. G. Cox, A. K. Hastings, K. L. Boyd, J.     Wadia, Z. Chen, D. R. Burton, R. A. Williamson, J. V. Williams, A     broadly neutralizing human monoclonal antibody exhibits in vivo     efficacy against both human metapneumovirus and respiratory     syncytial virus. J Infect Dis 211, 216-225 (2015). -   51. B. F. Fernie, P. J. Cote, Jr., J. L. Gerin, Classification of     hybridomas to respiratory syncytial virus glycoproteins. Proceedings     of the Society for Experimental Biology and Medicine. Society for     Experimental Biology and Medicine (New York, N.Y.) 171, 266-271     (1982). -   52. P. J. Cote, Jr., B. F. Fernie, E. C. Ford, J. W. Shih, J. L.     Gerin, Monoclonal antibodies to respiratory syncytial virus:     detection of virus neutralization and other antigen-antibody systems     using infected human and murine cells. Journal of virological     methods 3, 137-147 (1981). -   53. E. E. Walsh, J. Hruska, Monoclonal antibodies to respiratory     syncytial virus proteins: identification of the fusion protein. J     Virol 47, 171-177 (1983). -   54. L. J. Anderson, P. Bingham, J. C. Hierholzer, Neutralization of     respiratory syncytial virus by individual and mixtures of F and G     protein monoclonal antibodies. J Virol 62, 4232-4238 (1988). -   55. G. E. Scopes, P. J. Watt, P. R. Lambden, Identification of a     linear epitope on the fusion glycoprotein of respiratory syncytial     virus. J Gen Virol 71 (Pt 1), 53-59 (1990). -   56. J. Arbiza, G. Taylor, J. A. Lopez, J. Furze, S. Wyld, P.     Whyte, E. J. Stott, G. Wertz, W. Sullender, M. Trudel, et al.,     Characterization of two antigenic sites recognized by neutralizing     monoclonal antibodies directed against the fusion glycoprotein of     human respiratory syncytial virus. J Gen Virol 73 (Pt 9), 2225-2234     (1992). -   57. J. A. Lopez, R. Bustos, C. Orvell, M. Berois, J. Arbiza, B.     Garcia-Barreno, J. A. Melero, Antigenic structure of human     respiratory syncytial virus fusion glycoprotein. J Virol 72,     6922-6928 (1998). -   58. B. J. DeKosky, T. Kojima, A. Rodin, W. Charab, G. C.     Ippolito, A. D. Ellington, G. Georgiou, In-depth determination and     analysis of the human paired heavy- and light-chain antibody     repertoire. Nat Med 21, 86-91 (2015). -   59. U.S. National Library of Medicine, (NCT02290340,     https://clinicaltrials.gov/). -   60. PATH, RSV Vaccine Snapshot (2016     http://sites.path.org/vaccinedevelopment/files/2016/07/RSV-snapshot-July_13_2016.pdf). -   61. B. S. Graham, M. D. Perkins, P. F. Wright, D. T. Karzon, Primary     respiratory syncytial virus infection in mice. Journal of medical     virology 26, 153-162 (1988). -   62. A. L. Hotard, F. Y. Shaikh, S. Lee, D. Yan, M. N. Teng, R. K.     Plemper, J. E. Crowe, Jr., M. L. Moore, A stabilized respiratory     syncytial virus reverse genetics system amenable to     recombination-mediated mutagenesis. Virology 434, 129-136 (2012).

An informal sequence listing is provided in Table 6, below. The informal sequence listing provides the following sixteen (16) sequence elements contained in each of the 123 antibodies, identified as described above and designated as Antibody Numbers (Ab #) 1 through 123, in the following order:

-   -   Heavy chain variable region (“HC”) nucleic acid sequence     -   Heavy chain variable region (“HC”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) nucleic acid sequence     -   Heavy chain variable region CDR H2 (“H2”) amino acid sequence     -   Heavy chain variable region CDR H2 (“H2”) nucleic acid sequence     -   Heavy chain variable region CDR H3 (“H3”) amino acid sequence     -   Heavy chain variable region CDR H3 (“H3”) nucleic acid sequence     -   Light chain variable region (“LC”) nucleic acid sequence     -   Light chain variable region (“LC”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) nucleic acid sequence     -   Light chain variable region CDR L2 (“L2”) amino acid sequence     -   Light chain variable region CDR L2 (“L2”) nucleic acid sequence     -   Light chain variable region CDR L3 (“L3”) amino acid sequence     -   Light chain variable region CDR L3 (“L3”) nucleic acid sequence

TABLE 6 Informal Sequence Listing Seq. SEQ Antibody Ref. ID No. No. NO. Sequence 1 1 1 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAGGTGTCCTGCAGGGCTTCTGGATTCGTCTTCACCAGTTA TGATATCAACTGGGTGCGACAGGCCCCGGGGCAAGGTCTTGAGTGGA TGGGGCGAATGAACGCTCACACTGGACAGGTGACGTATGCCCAGAAA TTCCAGGACAAAGTCTCCATGACCAGGGACGTCTCCATAACGACAGC CTACCTGGAACTGAGTCGCCTGGCATCTGAGGACACGGCCGTCTATT ACTGTGCGAGGCCCGACATTAACTGGGGTCAAGATGCTTTTGATGTCT GGGGCCAGGGCACAATGGTCACCGTCTCTTCA 1 2 2 QVQLVQSGAEVKKPGASVKVSCRASGFVFTSYDINWVRQAPGQGLEW MGRMNAHTGQVTYAQKFQDKVSMTRDVSITTAYLELSRLASEDTAVYY CARPDINWGQDAFDVWGQGTMVTVSS 1 3 3 FVFTSYDIN 1 4 4 TTCGTCTTCACCAGTTATGATATCAAC 1 5 5 RMNAHTGQVTYAQKFQD 1 6 6 CGAATGAACGCTCACACTGGACAGGTGACGTATGCCCAGAAATTCCA GGAC 1 7 7 ARPDINWGQDAFDV 1 8 8 GCGAGGCCCGACATTAACTGGGGTCAAGATGCTTTTGATGTC 1 9 9 GACATCCGGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTATAGGA GCCAGAGTCACCATCACTTGCCGGGCCAGTCAGAATATTGGTAACTT CTTGGCCTGGTATCAGCAGAAGCCAGGGAAAGCCCCTAAACTCCTGA TCTATAAGGCGTCTACTTTAGATCCTGGGGTCCCATCAAGGTTCAGCG GCAGCGGATCTGGGACAGAATTCACTCTCACCATCACCAGCCTGCAG CCTGATGATTTCGCAACATTTTACTGCCAACAGTATAAGAGTGACCCC ACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 1 10 10 DIRMTQSPSTLSASIGARVTITCRASQNIGNFLAWYQQKPGKAPKLLIYK ASTLDPGVPSRFSGSGSGTEFTLTITSLQPDDFATFYCQQYKSDPTFGQGT KVEIK 1 11 11 RASQNIGNFLA 1 12 12 CGGGCCAGTCAGAATATTGGTAACTTCTTGGCC 1 13 13 KASTLDP 1 14 14 AAGGCGTCTACTTTAGATCCT 1 15 15 QQYKSDPT 1 16 16 CAACAGTATAAGAGTGACCCCACT 2 17 17 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC ATCGGTGAGGGTCTCCTGTAGGGCTTCAGGAGTCACTTTGACCACCGT TGCTGTCAACTGGGTGCGCCAGGTCCCTGGGCAAGGGCCTGAGTGGA TTGGAGGGATCCTCGTTGGGCTTGGTAAGGTCAGACTCGCCCAGAAA TTTGAGAATCGAGCCACTCTAAGGGCGGACACATCTAGCAACACAGC CTACATGGAGTTGAGCGGCCTGAGATTTGAGGACACGGCCGTCTATT ATTGTGCGATAATCGACCCCCAAGATTGTACTGCTGCCAGCTGCTTTT GGGTCAACTGGCTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTC TCCTCA 2 18 18 QVQLVQSGAEVKKPGSSVRVSCRASGVTLTTVAVNWVRQVPGQGPEWI GGILVGLGKVRLAQKFENRATLRADTSSNTAYMELSGLRFEDTAVYYCA IIDPQDCTAASCFWVNWLDPWGQGTLVTVSS 2 19 19 VTLTTVAVN 2 20 20 GTCACTTTGACCACCGTTGCTGTCAAC 2 21 21 GILVGLGKVRLAQKFEN 2 22 22 GGGATCCTCGTTGGGCTTGGTAAGGTCAGACTCGCCCAGAAATTTGA GAAT 2 23 23 AIIDPQDCTAASCFWVNWLDP 2 24 24 GCGATAATCGACCCCCAAGATTGTACTGCTGCCAGCTGCTTTTGGGTC AACTGGCTCGACCCC 2 25 25 GAAATTGTATTGACGCAGTCTCCAGGCACCCTGACCTTGTCTCCAGGG GAGACAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTCTTAGTGG CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCC TCATCTATGCTGCATCCACTAGGGCCACTGACATCCCAGCGAGGTTCA CTGGCAGTGGGTCTGCGACAGACTTCACTCTCACCATCAGCAGACTG GAGCCTCAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTTCGGCT CCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 2 26 26 EIVLTQSPGTLTLSPGETATLSCRASQSVLSGYLAWYQQKPGQAPRLLIY AASTRATDIPARFTGSGSATDFTLTISRLEPQDFAVYYCQQYGSAPITFGQ GTRLEIK 2 27 27 RASQSVLSGYLA 2 28 28 AGGGCCAGTCAGAGTGTTCTTAGTGGCTACTTAGCC 2 29 29 AASTRAT 2 30 30 GCTGCATCCACTAGGGCCACT 2 31 31 QQYGSAPIT 2 32 32 CAGCAGTATGGTTCGGCTCCGATCACC 3 33 33 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTAAAGAAGCCTGGGTC ATCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCATCAACAACG TTGCTATCAGTTGGCTGCGACAGGCCCCTGGACAAGGCCTGGAGTGG CTGGGAGGGAACATCCCTGGCTTTGGTAAAGTCAGATACTCACAGCA GTTTGAGACCAGACTCACTTTAACCGCGGACGTCTCGTCCGACACAG CCTACATGGTGTTGACCAGCCTAAGATCTGAAGACACGGCCGTCTATT ACTGTGCGATCATCGACCCCCAACTTTGCACCAGAGCCAGCTGCTTTT GGGTCAACTGGCTCGACCCCTGGGGCCAGGGGACCACGGTCACCGTC TCCTCA 3 34 34 QVQLVQSGAEVKKPGSSVKVSCKASGGTINNVAISWLRQAPGQGLEWL GGNIPGFGKVRYSQQFETRLTLTADVSSDTAYMVLTSLRSEDTAVYYCAI IDPQLCTRASCFWVNWLDPWGQGTTVTVSS 3 35 35 GTINNVAIS 3 36 36 GGCACCATCAACAACGTTGCTATCAGT 3 37 37 GNIPGFGKVRYSQQFET 3 38 38 GGGAACATCCCTGGCTTTGGTAAAGTCAGATACTCACAGCAGTTTGA GACC 3 39 39 AIIDPQLCTRASCFWVNWLDP 3 40 40 GCGATCATCGACCCCCAACTTTGCACCAGAGCCAGCTGCTTTTGGGTC AACTGGCTCGACCCC 3 41 41 GATATTGTGATGACTCAGTCTCCAGGCACCCTGTCTGTGTCTCCAGGG GAGAGTGCCGCCCTCTCCTGCGGGGCCAGTGAGAGTATTCTCAGCGA CTCCTTAGCCTGGTACCAGCATAAACCTGGTCAGGCTCCCAGGCTCCT CATCTATGGTGCATCCAGTAGGGCCGCTGGCATCCCAGACAGGTTCA GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG GAGCCAGAGGATTTTGCAGTGTATTTCTGTCAACAGTTTGGTGCCTTA CCGATCACTTTCGGCCAAGGGACACGACTGGAGATTAAA 3 42 42 DIVMTQSPGTLSVSPGESAALSCGASESILSDSLAWYQHKPGQAPRLLIY GASSRAAGIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQFGALPITFGQ GTRLEIK 3 43 43 GASESILSDSLA 3 44 44 GGGGCCAGTGAGAGTATTCTCAGCGACTCCTTAGCC 3 45 45 GASSRAA 3 46 46 GGTGCATCCAGTAGGGCCGCT 3 47 47 QQFGALPIT 3 48 48 CAACAGTTTGGTGCCTTACCGATCACT 4 49 49 CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCGGGGTC CTCGGTGAAAATCTCCTGTAAGGCTTCTGGAGGCACCTTCAACAGTCA AGCAATTCACTGGGTGCGACAGGCCCCTGGACAAGACCTTGAGTGGA TGGGAAACATCATCCCTGGGTTCGGATCACCAAACTCCGCGCAGAAC TTCCAGGGCAGGGTCACCTTCATTGCGGACGATTCCACTGGCGCTGCC TACATGGACTTGAGTAGCCTGAAGTCTGAAGACACGGCCGTCTATTA CTGTGCGACAGCCGGGTGGTTCGGGGAATCAGTTCATTTGGACTCAT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 4 50 50 QVQLVQSGAEVKKPGSSVKISCKASGGTFNSQAIHWVRQAPGQDLEWM GNIIPGFGSPNSAQNFQGRVTFIADDSTGAAYMDLSSLKSEDTAVYYCAT AGWFGESVHLDSWGQGTLVTVSS 4 51 51 GTFNSQAIH 4 52 52 GGCACCTTCAACAGTCAAGCAATTCAC 4 53 53 NIIPGFGSPNSAQNFQG 4 54 54 AACATCATCCCTGGGTTCGGATCACCAAACTCCGCGCAGAACTTCCA GGGC 4 55 55 ATAGWFGESVHLDS 4 56 56 GCGACAGCCGGGTGGTTCGGGGAATCAGTTCATTTGGACTCA 4 57 57 GATATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCAGTGAGAGTGTTAGCAGCAA CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG GCAGTGGGTCAGGGACGGAGTTCACTCTCACCATCAACAGCCTGCAG TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCT CCTCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 4 58 58 DIVMTQSPATLSVSPGERATLSCRASESVSSNLAWYQQKPGQAPRLLIYG ASTRATGIPARFSGSGSGTEFTLTINSLQSEDFAVYYCQQYNNWPPLTFG GGTKVEIK 4 59 59 RASESVSSNLA 4 60 60 AGGGCCAGTGAGAGTGTTAGCAGCAACTTAGCC 4 61 61 GASTRAT 4 62 62 GGTGCATCCACCAGGGCCACT 4 63 63 QQYNNWPPLT 4 64 64 CAGCAGTATAATAACTGGCCTCCTCTCACT 5 65 65 CAGGTCCAGCTGGTACAGTCTGGAAGTGAGGTGAAGAAGCCTGGGGC CTCGGTGAAGGTCTCCTGCAAGGCCTCAGGTTACAGGTTTTCCAACTA TGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGCCTAGAGTGGA TGGGATGGATCAGCGCTTACAATGGAAACATAAAGTATGGAAATAAC CTCCAGGGCAGAGTCACCGTGACCACAGACACATCCACGGCCACGGC CTACATGGAGGTGAGGAGCCTGACATCTGACGACACGGCCGTGTATT ACTGTGCGAGAGATGTCCCAGCTGACGGGGTCCACTTCATGGACGTC TGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA 5 66 66 QVQLVQSGSEVKKPGASVKVSCKASGYRFSNYGISWVRQAPGQGLEWM GWISAYNGNIKYGNNLQGRVTVTTDTSTATAYMEVRSLTSDDTAVYYC ARDVPADGVHFMDVWGQGTLVTVSS 5 67 67 YRFSNYGIS 5 68 68 TACAGGTTTTCCAACTATGGTATCAGC 5 69 69 WISAYNGNIKYGNNLQG 5 70 70 TGGATCAGCGCTTACAATGGAAACATAAAGTATGGAAATAACCTCCA GGGC 5 71 71 ARDVPADGVHFMDV 5 72 72 GCGAGAGATGTCCCAGCTGACGGGGTCCACTTCATGGACGTC 5 73 73 GAAATTGTAATGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTACACAGT GATACTAACACCTACTTGAACTGGTTTCAGCAGAGGCCAGGCCAATC TCCACGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTACTTTCACACTGAAAA TCAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCAG GGTTCACACTGGGCTCCGACTTTCGGCCAGGGGACCAAGGTGGAAAT CAAA 5 74 74 EIVMTQSPLSLPVTLGQPASISCRSSQSLVHSDTNTYLNWFQQRPGQSPRR LIYKVSNRDSGVPDRFSGSGSGTTFTLKISRVEAEDVGIYYCMQGSHWAP TFGQGTKVEIK 5 75 75 RSSQSLVHSDTNTYLN 5 76 76 AGGTCTAGTCAAAGCCTCGTACACAGTGATACTAACACCTACTTGAAC 5 77 77 KVSNRDS 5 78 78 AAGGTTTCTAACCGGGACTCT 5 79 79 MQGSHWAPT 5 80 80 ATGCAGGGTTCACACTGGGCTCCGACT 6 81 81 CAGGTCCAGCTGGTGCAGTCTGGGACTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCGGCAGCT ACGCTGTCATCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAATGG ATGGGACATTTCATCCCTGTGTTTGCTACAACAAACAAGGCACAGAA GTTCCAGGGCAGACTCACCCTTAGTACAGACGAATCTACGGGCACAG TCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTCTAT TTCTGTGCGACCAAGAGATATTGTAGTGATCCCAGCTGCCATGGACTC TGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTCCTCA 6 82 82 QVQLVQSGTEVKKPGSSVKVSCKASGGTFGSYAVIWVRQAPGQGLEWM GHFIPVFATTNKAQKFQGRLTLSTDESTGTVYMELSSLRSEDTAVYFCAT KRYCSDPSCHGLWYFDLWGRGTLVTVSS 6 83 83 GTFGSYAVI 6 84 84 GGCACCTTCGGCAGCTACGCTGTCATC 6 85 85 HFIPVFATTNKAQKFQG 6 86 86 CATTTCATCCCTGTGTTTGCTACAACAAACAAGGCACAGAAGTTCCAG GGC 6 87 87 ATKRYCSDPSCHGLWYFDL 6 88 88 GCGACCAAGAGATATTGTAGTGATCCCAGCTGCCATGGACTCTGGTA CTTCGATCTC 6 89 89 GACATCCAGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCTTGGATAGT GATGATGGAAACACCTATTTGGACTGGTACCTGCAGAAGCCAGGGCA GTCTCCACAGGTCCTGATCTATATGCTTTCGTATCGGGCCTCTGGAGT CCCAGACAGGTTCAGTGGCAGTGGGTCAGGCACTGATTTCACACTAG AAATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATG CAACGTGTAGAGTTTCCTTACACTTTTGGCCAGGGGACCAAGCTGGA GATCAAA 6 90 90 DIQLTQSPLSLPVTPGEPASISCRSSQSLLDSDDGNTYLDWYLQKPGQSPQ VLIYMLSYRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYCMQRVEFP YTFGQGTKLEIK 6 91 91 RSSQSLLDSDDGNTYLD 6 92 92 AGGTCTAGTCAGAGCCTCTTGGATAGTGATGATGGAAACACCTATTT GGAC 6 93 93 MLSYRAS 6 94 94 ATGCTTTCGTATCGGGCCTCT 6 95 95 MQRVEFPYT 6 96 96 ATGCAACGTGTAGAGTTTCCTTACACT 7 97 97 CAGGTCCAGCTGGTGCAGTCTGGGCCTGACGTGAAGAGACCTGGGGC CTCAGTGAGAGTCTCCTGCAAGGCTTCTGGATACACCTTCAGCGACTA CTATATGCACTGGGTGCGACAGGCCCCTGGACAGGGTCTTGAATGGC TGGCTTGGGTCAACCCTAGCACTGGCGCCACACACTACTCAGAGAGT TTTCGGGGCTCTATGGTCGTTCAAAGGGACACGTCCACCGACACAGC CTACCTGGAGCTGAGTAGTCTGAAATCTGACGACACGGCCGTCTATT ATTGTGCGAGAATCGGGAGTAATGAGATTTGGGGCCAGGGGACAATG GTCACCGTCTCTTCA 7 98 98 QVQLVQSGPDVKRPGASVRVSCKASGYTFSDYYMHWVRQAPGQGLEW LAWVNPSTGATHYSESFRGSMVVQRDTSTDTAYLELSSLKSDDTAVYYC ARIGSNEIWGQGTMVTVSS 7 99 99 YTFSDYYMH 7 100 100 TACACCTTCAGCGACTACTATATGCAC 7 101 101 WVNPSTGATHYSESFRG 7 102 102 TGGGTCAACCCTAGCACTGGCGCCACACACTACTCAGAGAGTTTTCG GGGC 7 103 103 ARIGSNEI 7 104 104 GCGAGAATCGGGAGTAATGAGATT 7 105 105 CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCGCTGGCACTTCCAGTGACATTGGTGGTTGG AACTATGTCTCCTGGTACCAACAGTACCCCGGCCAAGTCCCCAAACTC ATCCTTTATGAAGTCACTGATAGGCCCTCAGGGGTTTCTCATCGCTTC TCTGGCTCCAAGTCTGGCAACAGGGCCTTCCTTACCATCACTGGGCTC CGGGCCGAGGACGAGGCTGATTATTACTGCTGCTCATTTACTTCTTCC GGCAGTAGGGTTTTCGGCGGAGGGACCAAGGTCACCGTCCTA 7 106 106 QSALTQPASVSGSPGQSITISCAGTSSDIGGWNYVSWYQQYPGQVPKLIL YEVTDRPSGVSHRFSGSKSGNRAFLTITGLRAEDEADYYCCSFTSSGSRV FGGGTKVTVL 7 107 107 AGTSSDIGGWNYVS 7 108 108 GCTGGCACTTCCAGTGACATTGGTGGTTGGAACTATGTCTCC 7 109 109 EVTDRPS 7 110 110 GAAGTCACTGATAGGCCCTCA 7 111 111 CSFTSSGSRV 7 112 112 TGCTCATTTACTTCTTCCGGCAGTAGGGTT 8 113 113 GAGGTGCAGCTGTTGGAGTCTGGGGCTGTGATGAAGAGGCCTGGGTC ATCGGTGAGGGTCTCCTGCAGGGCTTCAGGAGTCACTTTGACCACCGT TTCTGTCAACTGGGTGCGCCAGGTCCCTGGGCAAGGGCCTGAGTGGA TTGGAGGGATCCTCATTGGGTTTGGTAAGGTCAGACAAGCCCAGAAA TTTGAGAACCGAGTCACTCTGACCGCGGACGCATCAAGGAACACAGC ATATATGGAGTTGAGCGGACTGACATCTGACGACACGGCCGTCTATT ACTGTGCGATAATCGACCCCCAAGATTGTACTCGTGCCAGCTGCTTTT GGGTCAACTGGCTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTC TCCTCA 8 114 114 EVQLLESGAVMKRPGSSVRVSCRASGVTLTTVSVNWVRQVPGQGPEWI GGILIGFGKVRQAQKFENRVTLTADASRNTAYMELSGLTSDDTAVYYCA IIDPQDCTRASCFWVNWLDPWGQGTLVTVSS 8 115 115 VTLTTVSVN 8 116 116 GTCACTTTGACCACCGTTTCTGTCAAC 8 117 117 GILIGFGKVRQAQKFEN 8 118 118 GGGATCCTCATTGGGTTTGGTAAGGTCAGACAAGCCCAGAAATTTGA GAAC 8 119 119 AIIDPQDCTRASCFWVNWLDP 8 120 120 GCGATAATCGACCCCCAAGATTGTACTCGTGCCAGCTGCTTTTGGGTC AACTGGCTCGACCCC 8 121 121 GACATCCGGATGACCCAGTCTCCAGGCACCCTGACCTTGTCCCCAGG GGAGCGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTCTTAGCG GGAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTC CTCATCTCTGCTGCATCCACTAGGGCCACTGACATCCCAGACAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCACCAGACT GGAGCCTCAAGATTTTGCAGTGTATTACTGTCAGCAGTATGATTCGGC TCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 8 122 122 DIRMTQSPGTLTLSPGERATLSCRASQSILSGNLAWYQQKPGQAPRLLISA ASTRATDIPDRFSGSGSGTDFTLTITRLEPQDFAVYYCQQYDSAPITFGQG TRLEIK 8 123 123 RASQSILSGNLA 8 124 124 AGGGCCAGTCAGAGTATTCTTAGCGGGAACTTAGCC 8 125 125 AASTRAT 8 126 126 GCTGCATCCACTAGGGCCACT 8 127 127 QQYDSAPIT 8 128 128 CAGCAGTATGATTCGGCTCCGATCACC 9 129 129 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCGAGGCTTCTGGAGACACCTTCACCAGTTA TGCAGTCATCTGGGTGCGCCAGACCCCAGGACAAGGGCTTGAGTTCA TGGGAAGTATCATCCCTATCTTTCAAACAATAAACTACGCTCCGAAGT TCCAGGGGAGGGTCACCCTAAGCGCGGACGGATCCACGAGCACAGTC TTCATGGAGTTGCGAAACCTGAGATCTGAGGACACGGCCATATATTT CTGTGCGACCAAGAGATATTGTACTAGTCCCAGCTGCCATGGACTCTG GTACTTCAATCTCTGGGGCCGTGGCACAATGGTCACCGTCTCTTCA 9 130 130 QVQLVQSGAEVKKPGSSVKVSCEASGDTFTSYAVIWVRQTPGQGLEFM GSIIPIFQTINYAPKFQGRVTLSADGSTSTVFMELRNLRSEDTAIYFCATKR YCTSPSCHGLWYFNLWGRGTMVTVSS 9 131 131 DTFTSYAVI 9 132 132 GACACCTTCACCAGTTATGCAGTCATC 9 133 133 SIIPIFQTINYAPKFQG 9 134 134 AGTATCATCCCTATCTTTCAAACAATAAACTACGCTCCGAAGTTCCAG GGG 9 135 135 ATKRYCTSPSCHGLWYFNL 9 136 136 GCGACCAAGAGATATTGTACTAGTCCCAGCTGCCATGGACTCTGGTA CTTCAATCTC 9 137 137 GAAACGACACTCACGCAGTCTCCAATCTCCCTGTCCGTCACCCCTGGA GAGCCGGCCTCCATCTCCTGCAGGTCTAGTAAGAGCCTCTTGGATAGT GATGATGGAAACACTTATTTGGACTGGTACCTGCAGAAGCCAGGGCA GTCTCCACAGATCCTGATCTATATGCTTTCGTATCGGGCCTCTGGAGT CCCAGACAGGTTCAGTGGCAGTGGGTCAGGCACTGATTTCACACTGA AAATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATG CAACGTATAGAGTATCCTTACACTTTTGGCCAGGGGACCAAGGTGGA GATCAAA 9 138 138 ETTLTQSPISLSVTPGEPASISCRSSKSLLDSDDGNTYLDWYLQKPGQSPQI LIYMLSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEYPY TFGQGTKVEIK 9 139 139 RSSKSLLDSDDGNTYLD 9 140 140 AGGTCTAGTAAGAGCCTCTTGGATAGTGATGATGGAAACACTTATTTG GAC 9 141 141 MLSYRAS 9 142 142 ATGCTTTCGTATCGGGCCTCT 9 143 143 MQRIEYPYT 9 144 144 ATGCAACGTATAGAGTATCCTTACACT 10 145 145 CAGGTGCAGCTGGTGCAATCTGGGGCTGAGATGAAGAAGCCTGGGTC CTCGGTGACAGTCTCCTGCAAGGCTTCTGGAGTCCCCTTCACCAGTTA TACCTACAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGAAGGGTCCTCCCTGTCATAGGTTCGGCAAAGTACCCACAGAAG TTCCAGGGCACAGTCACCATTACCGCGGACAAATCCACGAGCACAAT ATATTTGCAACTGAGCAGCCTAAGACCTGAAGACACGGCCATTTATTT CTGTGCGGGAAGTCTACTGGCTGGGTACGACAGGGAATTTGACTCCT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 10 146 146 QVQLVQSGAEMKKPGSSVTVSCKASGVPFTSYTYSWVRQAPGQGLEW MGRVLPVIGSAKYPQKFQGTVTITADKSTSTIYLQLSSLRPEDTAIYFCAG SLLAGYDREFDSWGQGTLVTVSS 10 147 147 VPFTSYTYS 10 148 148 GTCCCCTTCACCAGTTATACCTACAGC 10 149 149 RVLPVIGSAKYPQKFQG 10 150 150 AGGGTCCTCCCTGTCATAGGTTCGGCAAAGTACCCACAGAAGTTCCA GGGC 10 151 151 AGSLLAGYDREFDS 10 152 152 GCGGGAAGTCTACTGGCTGGGTACGACAGGGAATTTGACTCC 10 153 153 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGCATCTGTGGGA GACAGAATCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAACTG GTTAGCCTGGTATCAGCAGAAGCCAGGGAAAGCCCCTAAGTCCCTGA TCTATGAAGCATCCACTTTGCAAAGTGGGGTTTCATCAAGGTTCAGCG GCAGTGGATCTGGGACACACTTCACTCTCACCATCGCCAGCCTGCAG CCTGAAGATTTTGCAACTTATTACTGCCAACAGTATTATATTTACCCG CTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA 10 154 154 DIQMTQSPSSLSASVGDRITITCRASQGISNWLAWYQQKPGKAPKSLIYE ASTLQSGVSSRFSGSGSGTHFTLTIASLQPEDFATYYCQQYYIYPLTFGGG TKLEIK 10 155 155 RASQGISNWLA 10 156 156 CGGGCGAGTCAGGGTATTAGCAACTGGTTAGCC 10 157 157 EASTLQS 10 158 158 GAAGCATCCACTTTGCAAAGT 10 159 159 QQYYIYPLT 10 160 160 CAACAGTATTATATTTACCCGCTCACT 11 161 161 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGG GTCCCTAAGGCTCTCCTGTGCAGCCTCTGGAAGCTCCTTCCGTTATTC CTACATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGCAGTGGG TTGCATCTATTAGTCCTAGTAGCACTTATACAGACTACGCAGACTCTG TGAAGGGCCGAAGCACCATCTCCAGAGACCACGACAAGATCTCTCTG CAAGTGAACAGCCTGAGAGGCGACGACACGGCCGTGTATTATTGTGT GAGACATATGAATTTGGTGATGGGGCCGTTCGCCTTTGATATCTGGGG CCGCGGGACAATGGTCACCGTCTCTTCA 11 162 162 EVQLVESGGGLVKPGGSLRLSCAASGSSFRYSYMSWVRQAPGKGLQWV ASISPSSTYTDYADSVKGRSTISRDHDKISLQVNSLRGDDTAVYYCVRHM NLVMGPFAFDIWGRGTMVTVSS 11 163 163 SSFRYSYMS 11 164 164 AGCTCCTTCCGTTATTCCTACATGAGT 11 165 165 SISPSSTYTDYADSVKG 11 166 166 TCTATTAGTCCTAGTAGCACTTATACAGACTACGCAGACTCTGTGAAG GGC 11 167 167 VRHMNLVMGPFAFDI 11 168 168 GTGAGACATATGAATTTGGTGATGGGGCCGTTCGCCTTTGATATC 11 169 169 CAGTCTGTCGTGACGCAGCCGCCCTCATTGTCTGGGGCCCCAGGGCA GAGGATCACCATTTCGTGCACTGGGAGCAGCTCCAACATCGGGGCAG GTTATGATGTAAACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA CTCCTCATCTATGCTAAGACCAATCGGCCCTCAGGGGTCCCTGAGCGC TTCTCTGGTTCCGAGTCTGGCACCTCCGCCTCCCTGGCCATCACTGGG CTCCAGCCTGAGGATGAGGCTGATTATTACTGCCAGTCATATGACAG GATCGGAATGTATGTCTTCGGAACTGGGACCAAGCTGACCGTCCTA 11 170 170 QSVVTQPPSLSGAPGQRITISCTGSSSNIGAGYDVNWYQQLPGTAPKLLIY AKTNRPSGVPERFSGSESGTSASLAITGLQPEDEADYYCQSYDRIGMYVF GTGTKLTVL 11 171 171 TGSSSNIGAGYDVN 11 172 172 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTAAAC 11 173 173 AKTNRPS 11 174 174 GCTAAGACCAATCGGCCCTCA 11 175 175 QSYDRIGMYV 11 176 176 CAGTCATATGACAGGATCGGAATGTATGTC 12 177 177 GAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTGGTAAAGCCTGGGGG GTCCCTCAGACTCTCATGTGAAGGCTCTGGCTTCATTTTTCCGAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGTATTAAAAGCAACACTGACGGTGGGACAACAGACTACGGT GCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAACAAA CACGATGTATCTGCACATGAACAGCCTGAAGACCGAGGACACAGCCG TGTATTTCTGTTCCACAGGCCCACCCTATAAGTATTTTGATGAGACTG GTTATTCGGTCGTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 12 178 178 EVQLVESGGDLVKPGGSLRLSCEGSGFIFPNAWMSWVRQAPGKGLEWV GRIKSNTDGGTTDYGAPVKGRFTISRDDSTNTMYLHMNSLKTEDTAVYF CSTGPPYKYFDETGYSVVDYWGQGTLVTVSS 12 179 179 FIFPNAWMS 12 180 180 TTCATTTTTCCGAACGCCTGGATGAGC 12 181 181 RIKSNTDGGTTDYGAPVKG 12 182 182 CGTATTAAAAGCAACACTGACGGTGGGACAACAGACTACGGTGCACC CGTGAAAGGC 12 183 183 STGPPYKYFDETGYSVVDY 12 184 184 TCCACAGGCCCACCCTATAAGTATTTTGATGAGACTGGTTATTCGGTC GTTGACTAC 12 185 185 TCCTATGAGCTGACACAGCCACCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCATCATCTCTTGTTCTGGAAGCACGTCCAATTCCGGATATAA TTATTTTTACTGGTATCAGCAGCGCCCAGGAACGGCCCCCAAACTCCT CATCTATGGCAGTGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTC TGGTTCCCAGTCTGGCCCCTCAGCCTCCCTGGCCATCAGTGGGCTCCG GTCCGAGGATGAGGCTCATTATTACTGTGCAGCGTGGGATGACAACC TGAGTGGTCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 12 186 186 SYELTQPPSASGTPGQRVIISCSGSTSNSGYNYFYWYQQRPGTAPKLLIYG SDQRPSGVPDRFSGSQSGPSASLAISGLRSEDEAHYYCAAWDDNLSGPVF GGGTKLTVL 12 187 187 SGSTSNSGYNYFY 12 188 188 TCTGGAAGCACGTCCAATTCCGGATATAATTATTTTTAC 12 189 189 GSDQRPS 12 190 190 GGCAGTGATCAGCGGCCCTCA 12 191 191 AAWDDNLSGPV 12 192 192 GCAGCGTGGGATGACAACCTGAGTGGTCCGGTG 13 193 193 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCGAAGACTCGCATGTGCAGCCTCTGGATTCATCTTCCGCAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGGATTAAAAGGACAAGTGAAGGAGGGTCAGTCGACTACGCG ACACCCGTGCAAGGCAGATTCTCCATCTCAAGAGATGATTCTAGAAA CACACTGTATCTACAAATGCACAGCCTGGCACCCGACGACACAGCCG TGTATTACTGTTCCACAGGCCCACCCTATTCTTACTTTGATAGTACTG GTTATTCGGTCGTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CTTCA 13 194 194 QVQLVQSGGGLVKPGGSRRLACAASGFIFRNAWMSWVRQAPGKGLEW VGRIKRTSEGGSVDYATPVQGRFSISRDDSRNTLYLQMHSLAPDDTAVY YCSTGPPYSYFDSTGYSVVDYWGQGTLVTVSS 13 195 195 FIFRNAWMS 13 196 196 TTCATCTTCCGCAACGCCTGGATGAGC 13 197 197 RIKRTSEGGSVDYATPVQG 13 198 198 CGGATTAAAAGGACAAGTGAAGGAGGGTCAGTCGACTACGCGACAC CCGTGCAAGGC 13 199 199 STGPPYSYFDSTGYSVVDY 13 200 200 TCCACAGGCCCACCCTATTCTTACTTTGATAGTACTGGTTATTCGGTC GTGGACTAC 13 201 201 CAGTCTGTGTTGACGCAGCCGCCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGCAAGCAGCTCCAACATCGGAGATA ATTATTTCTACTGGTACCAACAACTCCCAGGAAAGGCCCCCACACTCC TCATGTATGGTAGTGACCAGCGGTCCTCAGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCACCTCTGCCTCCCTGGCCATCAGTGGGCTCC GGTCCGAGGATGAAGCTGCTTATTATTGTGCAGCTTGGGATGACAGC CTGAGTGGTCCGGTGTTCGGCGGAGGCACCCAGCTGACCGTCCTC 13 202 202 QSVLTQPPSASGTPGQRVTISCSASSSNIGDNYFYWYQQLPGKAPTLLMY GSDQRSSGVPDRFSGSQSGTSASLAISGLRSEDEAAYYCAAWDDSLSGPV FGGGTQLTVL 13 203 203 SASSSNIGDNYFY 13 204 204 TCTGCAAGCAGCTCCAACATCGGAGATAATTATTTCTAC 13 205 205 GSDQRSS 13 206 206 GGTAGTGACCAGCGGTCCTCA 13 207 207 AAWDDSLSGPV 13 208 208 GCAGCTTGGGATGACAGCCTGAGTGGTCCGGTG 14 209 209 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAGGAAGCCTGGGG CCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACATCTTCATTAACT ACTATATACACTGGGTGCGACAGGCCCCTGGACAAGGTCTTGAGTGG ATGGGGTGGATCAACCCTAACAGTGGAGCCTCAAACCACGCACAGAC GTTCGAGGGCAGGATCACCATGACCACCGACACGTCCAGCAACACAG CCTACATGGAGCTGAGTAGACTGAGAGAGGACGACACGGCCGTCTAT TACTGTGCGAGATCCCAGCAACTGCTCGTTATCACCGATTACTCCTTA GACTACTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCA 14 210 210 EVQLVESGAEVRKPGASVKVSCKASGYIFINYYIHWVRQAPGQGLEWM GWINPNSGASNHAQTFEGRITMTTDTSSNTAYMELSRLREDDTAVYYCA RSQQLLVITDYSLDYWGLGTLVTVSS 14 211 211 YIFINYYIH 14 212 212 TACATCTTCATTAACTACTATATACAC 14 213 213 WINPNSGASNHAQTFEG 14 214 214 TGGATCAACCCTAACAGTGGAGCCTCAAACCACGCACAGACGTTCGA GGGC 14 215 215 ARSQQLLVITDYSLDY 14 216 216 GCGAGATCCCAGCAACTGCTCGTTATCACCGATTACTCCTTAGACTAC 14 217 217 TCCTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAG ACAGTCAGGATCACATGCCACGGAGACACCCTCAGAAACTATTATCC AGCCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTTCTTGTCGTGT CTGATAGAAACACCCGGCCCTCAGGGATCCCAGACCGATTCTCTGTCT CCACCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCG GAAGATGAGGGTGACTATTACTGTAACTGCCGCGACAGCAGTGGTCA CCGGCTGGTCTTCGGCGGAGGGACCAAGCTGACCGTCCTA 14 218 218 SSELTQDPAVSVALGQTVRITCHGDTLRNYYPAWYQQKPGQAPVLVVS DRNTRPSGIPDRFSVSTSGNTASLTITGAQAEDEGDYYCNCRDSSGHRLV FGGGTKLTVL 14 219 219 HGDTLRNYYPA 14 220 220 CACGGAGACACCCTCAGAAACTATTATCCAGCC 14 221 221 DRNTRPS 14 222 222 GATAGAAACACCCGGCCCTCA 14 223 223 NCRDSSGHRLV 14 224 224 AACTGCCGCGACAGCAGTGGTCACCGGCTGGTC 15 225 225 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCGAGGCTTCTGGAGACACCTTCACCAGTTA TGCAGTCATCTGGGTGCGCCAGGCCCCAGGACAAGGGCTTGAGTGGA TGGGAAGTATCATCCCTATCTTTCAAACAATCAACTACGCACCAAAGT TCCAGGGGAGGGTCACCCTAAGCGCGGACGGATCTACGAGAACAGTC TACATGGAGTTGGGAAGCCTGAGATCAGAGGACACGGCCATATATTT CTGTGCGACCAAGAGATACTGTACTAGTCCCAGCTGCCATGGACTCT GGTACTTCAATCTCTGGGGCCGTGGAACCCTGGTCACCGTCTCCTCA 15 226 226 QVQLVQSGAEVKKPGSSVKVSCEASGDTFTSYAVIWVRQAPGQGLEWM GSIIPIFQTINYAPKFQGRVTLSADGSTRTVYMELGSLRSEDTAIYFCATKR YCTSPSCHGLWYFNLWGRGTLVTVSS 15 227 227 DTFTSYAVI 15 228 228 GACACCTTCACCAGTTATGCAGTCATC 15 229 229 SIIPIFQTINYAPKFQG 15 230 230 AGTATCATCCCTATCTTTCAAACAATCAACTACGCACCAAAGTTCCAG GGG 15 231 231 ATKRYCTSPSCHGLWYFNL 15 232 232 GCGACCAAGAGATACTGTACTAGTCCCAGCTGCCATGGACTCTGGTA CTTCAATCTC 15 233 233 GATATTGTGATGACCCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA GAGCCGGCCTCCATCTCCTGCAGGTCTAGTAAGAGCCTCTTGGATAGT GATGATGGAAACACCTATTTGGACTGGTACCTGCAGAAGCCAGGGCA GTCTCCACAGATCCTGATCTATATGCTTTCGCATCGGGCCTCTGGAGT CCCAGACAGGTTCAGTGGCAGTGGGTCAGGCACTGACTTCACACTGA AAATCAGTAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATG CAACGTGTAGAGTATCCTTACAGTTTTGGCCAGGGGACCAAGGTGGA GATCAAA 15 234 234 DIVMTQSPLSLPVTPGEPASISCRSSKSLLDSDDGNTYLDWYLQKPGQSP QILIYMLSHRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRVEY PYSFGQGTKVEIK 15 235 235 RSSKSLLDSDDGNTYLD 15 236 236 AGGTCTAGTAAGAGCCTCTTGGATAGTGATGATGGAAACACCTATTT GGAC 15 237 237 MLSHRAS 15 238 238 ATGCTTTCGCATCGGGCCTCT 15 239 239 MQRVEYPYS 15 240 240 ATGCAACGTGTAGAGTATCCTTACAGT 16 241 241 CAGATCACCTTGAAGGAGTCTGGGCCTACCGTGGTGAAACCCACACA GACCCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAACACTCG TGGCATGGGTGTGGCCTGGATCCGTCAGCCCCCAGGAGGGGCCCTGG AGTGGCTTGCACTCGTTGATTGGGATGATGATAAGCGCTACAGCCCTT CTCTGAGGAGCAGGCTCACCATCACCAAAGACACGTCCAAGAACCAG GTGCTCTTTACAATGACCACCATGGACCCCGCGGACACAGCCACGTA CTACTGTGCACACATCGGTCTTTATGATCGTGGTGGCTATTACTTATT CTACTTTGACTTTTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 16 242 242 QITLKESGPTVVKPTQTLTLTCTFSGFSLNTRGMGVAWIRQPPGGALEWL ALVDWDDDKRYSPSLRSRLTITKDTSKNQVLFTMTTMDPADTATYYCA HIGLYDRGGYYLFYFDFWGQGTLVTVSS 16 243 243 FSLNTRGMGVA 16 244 244 TTCTCACTCAACACTCGTGGCATGGGTGTGGCC 16 245 245 LVDWDDDKRYSPSLRS 16 246 246 CTCGTTGATTGGGATGATGATAAGCGCTACAGCCCTTCTCTGAGGAGC 16 247 247 AHIGLYDRGGYYLFYFDF 16 248 248 GCACACATCGGTCTTTATGATCGTGGTGGCTATTACTTATTCTACTTTG ACTTT 16 249 249 GATATTGTGCTGACGCAGTCTCCATCCTCCCTGTCTGCGTCTGTAGGC GACAGGGTCACCATCACTTGCCGGGCAAGTCAGAGCATTGCCAGCTA TGTGAATTGGTTTCAGCAGAAACCAGGGAAAGCCCCTGTCCTCTTGAT GTTTGCTTCATCCATTTTGCAAAGTGGCGTCCCGCCAAGGTTCCGTGG CAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTCCAGCC TGAAGATTTTGCAACTTACTACTGTCAACACACTTACACCACCCCGTA CATTTTTGGCCGGGGGACCAAAGTGGAGATCAAA 16 250 250 DIVLTQSPSSLSASVGDRVTITCRASQSIASYVNWFQQKPGKAPVLLMFA SSILQSGVPPRFRGSGSGTDFTLTITSLQPEDFATYYCQHTYTTPYIFGRGT KVEIK 16 251 251 RASQSIASYVN 16 252 252 CGGGCAAGTCAGAGCATTGCCAGCTATGTGAAT 16 253 253 ASSILQS 16 254 254 GCTTCATCCATTTTGCAAAGT 16 255 255 QHTYTTPYI 16 256 256 CAACACACTTACACCACCCCGTACATT 17 257 257 CAGGTCCAGCTTGTGCAGTCTGGTCCTACGCTGGTGAAACCCACACA GACCCTCACGCTGACCTGCACCTTCTCTGGCTTCTCACTCAGCACTCG TGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGG AGTGCCTTGGATTCACTTATTGGGATGGTGATCAGTTCCACAGCCCAT CTCTGAAGAACAGACTCACCATTACCAAGGACACCTCCAAAAACCAG GTGGTCCTTAGAATGACCAACATGGACCCTGTGGACACGGCCACCTA TTTCTGTGTACACAGCGATCTCTATGATAGTGGTGGTTATTACTTGTA CTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 17 258 258 QVQLVQSGPTLVKPTQTLTLTCTFSGFSLSTRGVGVGWIRQPPGKALECL GFTYWDGDQFHSPSLKNRLTITKDTSKNQVVLRMTNMDPVDTATYFCV HSDLYDSGGYYLYYFDYWGQGTLVTVSS 17 259 259 FSLSTRGVGVG 17 260 260 TTCTCACTCAGCACTCGTGGAGTGGGTGTGGGC 17 261 261 FTYWDGDQFHSPSLKN 17 262 262 TTCACTTATTGGGATGGTGATCAGTTCCACAGCCCATCTCTGAAGAAC 17 263 263 VHSDLYDSGGYYLYYFDY 17 264 264 GTACACAGCGATCTCTATGATAGTGGTGGTTATTACTTGTACTACTTT GACTAC 17 265 265 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCTTCTGTGGGG GACAGAGTCACCATCACTTGCCGAGCCAGTCAGACCATTGCCAGTTA TTTAAATTGGTATCAGCAAAGACCAGGGGAAGCCCCTAAACTCTTGA TCTATGCTGCTTCCAGTTTGCAGAGTGGGGTCTCATCAAGATTCAGTG GCAGGGGATCTGGGACAGATTTCACTCTCACCATCAATATTCTACAAC CTGAGGATCTTGCAACTTACTTCTGTCAACAGGCTTACTCTGCCCCGT ACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 17 266 266 DIQMTQSPSSLSASVGDRVTITCRASQTIASYLNWYQQRPGEAPKLLIYA ASSLQSGVSSRFSGRGSGTDFTLTINILQPEDLATYFCQQAYSAPYTFGQG TKVEIK 17 267 267 RASQTIASYLN 17 268 268 CGAGCCAGTCAGACCATTGCCAGTTATTTAAAT 17 269 269 AASSLQS 17 270 270 GCTGCTTCCAGTTTGCAGAGT 17 271 271 QQAYSAPYT 17 272 272 CAACAGGCTTACTCTGCCCCGTACACT 18 273 273 CAGGTCCAGCTGGTACAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTA TGGTACCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAT CTCCAGGGCAGAGTCACCATGACCACAGACACATCAACGAGCACATC CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATT ACTGTGCGAGAGATGTCCCCGTCATAGCAGCTGGTACAATGGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 18 274 274 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGTSWVRQAPGQGLEW MGWISAYNGNTNYAQNLQGRVTMTTDTSTSTSYMELRSLRSDDTAVYY CARDVPVIAAGTMDYWGQGTLVTVSS 18 275 275 YTFTSYGTS 18 276 276 TACACCTTTACCAGCTATGGTACCAGC 18 277 277 WISAYNGNTNYAQNLQG 18 278 278 TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAATCTCCA GGGC 18 279 279 ARDVPVIAAGTMDY 18 280 280 GCGAGAGATGTCCCCGTCATAGCAGCTGGTACAATGGACTAC 18 281 281 GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGT GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC TCCAAGGCGCCTAATTTATAAGGTTTCTAATCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA GGTCCACACTGGCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAA 18 282 282 DIVMTQTPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPR RLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGPHW PRTFGQGTKVEIK 18 283 283 RSSQSLVYSDGNTYLN 18 284 284 AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAAT 18 285 285 KVSNRDS 18 286 286 AAGGTTTCTAATCGGGACTCT 18 287 287 MQGPHWPRT 18 288 288 ATGCAAGGTCCACACTGGCCTCGAACG 19 289 289 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAAGTCTCGTGTGAGGCCTCTGAATACAGTTTCAGTGGCG ACTATGTTCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGG ATGGGTTGGATAAAGGCTGTCAATGGTGGCGCGAACTACGCACAGAA GTTTCACGGCAGGGTCACAATGACCACTGACTCGTCCAAGAGCACAG TCTATTTGGAGATGAGCAGACTGACACCTGCCGACACGGCCATTTATT TTTGTGCGAAGGATCGGGCTGCAAGTGTTCATGTGCCAGCGGGCGCG TTTGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 19 290 290 QVQLVQSGAEVKKPGASVKVSCEASEYSFSGDYVHWVRQAPGQGLEW MGWIKAVNGGANYAQKFHGRVTMTTDSSKSTVYLEMSRLTPADTAIYF CAKDRAASVHVPAGAFDLWGQGTLVTVSS 19 291 291 YSFSGDYVH 19 292 292 TACAGTTTCAGTGGCGACTATGTTCAC 19 293 293 WIKAVNGGANYAQKFHG 19 294 294 TGGATAAAGGCTGTCAATGGTGGCGCGAACTACGCACAGAAGTTTCA CGGC 19 295 295 AKDRAASVHVPAGAFDL 19 296 296 GCGAAGGATCGGGCTGCAAGTGTTCATGTGCCAGCGGGCGCGTTTGA CCTC 19 297 297 GACATCCAGATGACCCAGTCTCCTTCCTCCCTGTCTGCATATGTAGGA GACAGAGTCAGCATCACTTGTCGGGCAAGTCAGAGCATTGACAACTT TTTAAATTGGTATCGGCAGAGACCAGGGAAAGCCCCTGAACTCCTAA TCTATGCTGCCTCCACTTTGCAAGGTGGGGTCCCATCAAGGTTCAGTG GCAGTGGATCTGGGACACATTTCACTCTCACCATCAGCAGTCTCCAGC CTGAAGATTTTGCCACTTACTACTGTCAACAGAGTTTCACTATTCCTT CGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 19 298 298 DIQMTQSPSSLSAYVGDRVSITCRASQSIDNFLNWYRQRPGKAPELLIYA ASTLQGGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQSFTIPSITFGQG TRLEIK 19 299 299 RASQSIDNFLN 19 300 300 CGGGCAAGTCAGAGCATTGACAACTTTTTAAAT 19 301 301 AASTLQG 19 302 302 GCTGCCTCCACTTTGCAAGGT 19 303 303 QQSFTIPSIT 19 304 304 CAACAGAGTTTCACTATTCCTTCGATCACC 20 305 305 CAGGTCACCTTGAAGGAGTCTGGTCCTGCGCTGGTGAGACCCAAACA GACCCTCACTCTGACCTGCTCCTTCTCCGGCTTCTCACTCGACACTCA AAGAACGGGTGTGAATTGGATCCGTCAGTCCCCAGGGAAGGCCCTGG AGTGGCTTGCACGGATTGATTGGGATGGCAATATTTACTCCAGCACCT CTGTGAGGACCAAACTCAGCATCTCCAAGGGCACCTCCAAAAACCAG GTGGTCCTTACAATGACCGACGTGGACCCTGTGGACACAGCCACCTA TTACTGTGCACGGACTCTTTACTATACTTCTGGTGGTTATTACTTGAAC CTCTTTGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA 20 306 306 QVTLKESGPALVRPKQTLTLTCSFSGFSLDTQRTGVNWIRQSPGKALEWL ARIDWDGNIYSSTSVRTKLSISKGTSKNQVVLTMTDVDPVDTATYYCAR TLYYTSGGYYLNLFDYWGQGTLVTVSS 20 307 307 FSLDTQRTGVN 20 308 308 TTCTCACTCGACACTCAAAGAACGGGTGTGAAT 20 309 309 RIDWDGNIYSSTSVRT 20 310 310 CGGATTGATTGGGATGGCAATATTTACTCCAGCACCTCTGTGAGGACC 20 311 311 ARTLYYTSGGYYLNLFDY 20 312 312 GCACGGACTCTTTACTATACTTCTGGTGGTTATTACTTGAACCTCTTTG ACTAC 20 313 313 GAAATTGTAATGACACAGTCTCCACCCTCCCTGTCTGCCTCTGTTGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGACAATTCCCAGCTA TGTCAATTGGTATCAGCAGATATCAGGGAAAGCCCCTCGCCTCCTGAT CTATGCTGCCTCACTTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGG CAGCGGATCTGGGACAGAGTTCAGTCTCACCATCAGCGGTCTGCGAC CTGAGGATTTTGGCACTTACTACTGTCAACAGAGTTACAGTTCCACTC CCACTTTCGGCCAGGGGACCAAGGTGGAAATCAAA 20 314 314 EIVMTQSPPSLSASVGDRVTITCRASQTIPSYVNWYQQISGKAPRLLIYAA SLLQSGVPSRFSGSGSGTEFSLTISGLRPEDFGTYYCQQSYSSTPTFGQGT KVEIK 20 315 315 RASQTIPSYVN 20 316 316 CGGGCAAGTCAGACAATTCCCAGCTATGTCAAT 20 317 317 AASLLQS 20 318 318 GCTGCCTCACTTTTGCAAAGT 20 319 319 QQSYSSTPT 20 320 320 CAACAGAGTTACAGTTCCACTCCCACT 21 321 321 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCTGAGACTCTCATGTGCAGCCTCTGGATTCATTTTCAGTAACGC CTGGATGAGTTGGGTCCGCCAGTCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGTATTAAAACCAAAACTGAGGGTGCGACAACAGACCACGCT GCACCCCTGAAAGGCAGATTCACCATCTCAAGAGATGATTCGAGAAA CACACTGTATCTCCAAATGGACAGCCTGACAACCGAGGACACAGCCG TGTATTTTTGTACCACAGGCCCACCTTATAGTTACTTTGACAGTACTG GGTATTCCATCGTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 21 322 322 QVQLVESGGGLVKPGGSLRLSCAASGFIFSNAWMSWVRQSPGKGLEWV GRIKTKTEGATTDHAAPLKGRFTISRDDSRNTLYLQMDSLTTEDTAVYFC TTGPPYSYFDSTGYSIVDYWGQGTLVTVSS 21 323 323 FIFSNAWMS 21 324 324 TTCATTTTCAGTAACGCCTGGATGAGT 21 325 325 RIKTKTEGATTDHAAPLKG 21 326 326 CGTATTAAAACCAAAACTGAGGGTGCGACAACAGACCACGCTGCACC CCTGAAAGGC 21 327 327 TTGPPYSYFDSTGYSIVDY 21 328 328 ACCACAGGCCCACCTTATAGTTACTTTGACAGTACTGGGTATTCCATC GTTGACTAC 21 329 329 TCTTATGAGCTGACACAGCCACCCGCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCCGGAAGCAGCTCCAACATCGGAAGTG AGTATGTATTGTGGTATCAGCAGGTCCCAGGAACGGCCCCCAAACTC CTCATCTATAATAGTCATCAGCGGCCCTCAGGGGTCCCTGACCGCATT TCTGGCTCCCGGTCTGGCACCTCTGCCTCCCTGGCCATCAGTGGGCTC CGGTCCGAGGATGAGGCTCATTATTACTGTGCATCCTGGGATGACAG CCTGAGTGGTCCGGTTTTCGGCGGAGGGACCCAGCTGACCGTCCTC 21 330 330 SYELTQPPAASGTPGQRVTISCSGSSSNIGSEYVLWYQQVPGTAPKLLIYN SHQRPSGVPDRISGSRSGTSASLAISGLRSEDEAHYYCASWDDSLSGPVF GGGTQLTVL 21 331 331 SGSSSNIGSEYVL 21 332 332 TCCGGAAGCAGCTCCAACATCGGAAGTGAGTATGTATTG 21 333 333 NSHQRPS 21 334 334 AATAGTCATCAGCGGCCCTCA 21 335 335 ASWDDSLSGPV 21 336 336 GCATCCTGGGATGACAGCCTGAGTGGTCCGGTT 22 337 337 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCTTAGACTCTCATGTGCAGCCTCTGGATTCACTTTCAGTAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGACTGGG TTGGCCGTATCAAAACCAAAGCTGATGGTGGGACAAGAGACTACGCT GCACCCGTGAAAGGCAGATTTACCATCTCGAGAGATGATTCAGAAAA CACGTTGTATCTGCAAATGACCAGCCTGAAAACCGAGGACACAGGCG TGTATTACTGTAGCACAGGCCCACCCTATAAATATCATGATAGTACTG GTTATTCGGTCGTTGACTACTGGGGCCAGGGAACCCTGGTCACTGTCT CCTCA 22 338 338 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLDW VGRIKTKADGGTRDYAAPVKGRFTISRDDSENTLYLQMTSLKTEDTGVY YCSTGPPYKYHDSTGYSVVDYWGQGTLVTVSS 22 339 339 FTFSNAWMS 22 340 340 TTCACTTTCAGTAACGCCTGGATGAGC 22 341 341 RIKTKADGGTRDYAAPVKG 22 342 342 CGTATCAAAACCAAAGCTGATGGTGGGACAAGAGACTACGCTGCACC CGTGAAAGGC 22 343 343 STGPPYKYHDSTGYSVVDY 22 344 344 AGCACAGGCCCACCCTATAAATATCATGATAGTACTGGTTATTCGGTC GTTGACTAC 22 345 345 TCTTATGAGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCCTGTTCTGGAGGCAGCTCCAACATCGGAAGTG ATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC CTCATCTATGGTAGTAGTCAGCGACCCTCAGGGGTCCCTGACCGATTC TCTGGCTCCCAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGTCTC CGGTCCGAGGATGAGGCTGATTATTACTGTGCTATGTGGGATGACAG CCTGAATGGTCCGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 22 346 346 SYELTQPPSASGTPGQRVTISCSGGSSNIGSDYVYWYQQLPGTAPKLLIYG SSQRPSGVPDRFSGSQSGTSASLAISGLRSEDEADYYCAMWDDSLNGPVF GGGTKLTVL 22 347 347 SGGSSNIGSDYVY 22 348 348 TCTGGAGGCAGCTCCAACATCGGAAGTGATTATGTATAC 22 349 349 GSSQRPS 22 350 350 GGTAGTAGTCAGCGACCCTCA 22 351 351 AMWDDSLNGPV 22 352 352 GCTATGTGGGATGACAGCCTGAATGGTCCGGTG 23 353 353 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGA GACCCTGTCCCTCTCCTGCACCGTCTCTGGTGGGGTCTTCGGCAATTA CTTTTGGAGTTGGGTCCGCCAGGCCCCAGGGAAGGGCCTGGAATGGA TTGGAGAAATCAATCAGATTGGAACCACCAACTACAGTCCGTCCGCG TCCCTCAAGAGTCGAGTCACTATATCAGTTGACCCGTCCAGGAACCA GTTCTCCCTGAGCCTGAGGTCTGTGACCGCCGCGGACACGGCTCGGT ATTACTGTACGAGATCCGAAACTTCAGATTACTTTGATAGTAGTGGTT ATGCATTTCATATCTGGGGCGAAGGGACAATGGTCACCGTCTCTTCA 23 354 354 QVQLQQWGAGLLKPSETLSLSCTVSGGVFGNYFWSWVRQAPGKGLEWI GEINQIGTTNYSPSASLKSRVTISVDPSRNQFSLSLRSVTAADTARYYCTR SETSDYFDSSGYAFHIWGEGTMVTVSS 23 355 355 GVFGNYFWS 23 356 356 GGGGTCTTCGGCAATTACTTTTGGAGT 23 357 357 EINQIGTTNYSPSASLKS 23 358 358 GAAATCAATCAGATTGGAACCACCAACTACAGTCCGTCCGCGTCCCT CAAGAGT 23 359 359 TRSETSDYFDSSGYAFHI 23 360 360 ACGAGATCCGAAACTTCAGATTACTTTGATAGTAGTGGTTATGCATTT CATATC 23 361 361 CTGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCAGTGGAATCAGCAGTGACGGTGGTCGCTAT AACTATGTGTCCTGGTACCAACAACACCCGGGCAAAGCCCCCAAACT CCTCATCTATGATGACAGTAATTGGCCTTTAGGGGTTTCTCATCGCTT CTCTGGGTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT CCGGGCTGAGGACGAGGCGGACTATTATTGCGGCTCATATACGGACA CCAACAGACTCTTCGGCGGAGGCACCCAGCTGACCGTCCTC 23 362 362 LPVLTQPASVSGSPGQSITISCSGISSDGGRYNYVSWYQQHPGKAPKLLIY DDSNWPLGVSHRFSGSKSGNTASLTISGLRAEDEADYYCGSYTDTNRLF GGGTQLTVL 23 363 363 SGISSDGGRYNYVS 23 364 364 AGTGGAATCAGCAGTGACGGTGGTCGCTATAACTATGTGTCC 23 365 365 DDSNWPL 23 366 366 GATGACAGTAATTGGCCTTTA 23 367 367 GSYTDTNRL 23 368 368 GGCTCATATACGGACACCAACAGACTC 24 369 369 GAGGTGCAGCTGGTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGA GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACC ATGCTATGTACTGGGTCCGCCAGGCTCCAGGCAAAGGGCTAGAGTGG GTGGCACTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCC GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT GTATCTGCAGATGAACAGCCTGAGAGCTGAGGACACGGCTGTCTATT ACTGTGCGAGAGATCAATGGCTGGTTCCTGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 24 370 370 EVQLVESGGGVVQPGRSLRLSCAASGFTFSDHAMYWVRQAPGKGLEW VALISFDGRNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDQWLVPDYWGQGTLVTVSS 24 371 371 FTFSDHAMY 24 372 372 TTCACCTTCAGTGACCATGCTATGTAC 24 373 373 LISFDGRNIYYADSVKG 24 374 374 CTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCCGTGAA GGGC 24 375 375 ARDQWLVPDY 24 376 376 GCGAGAGATCAATGGCTGGTTCCTGACTAC 24 377 377 CTGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTATGTCTCCTGGTACCAACAGCACCCAGGCAACGCCCCCAAACT CATGATTTATGAAGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT CTCTGGCTTCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA GCAACAGTGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 24 378 378 LPVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGNAPKLMI YEVSKRPSGVPDRFSGFKSGNTASLTVSGLQAEDEADYYCSSYAGSNSV FGTGTKLTVL 24 379 379 TGTSSDVGGYNYVS 24 380 380 ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCC 24 381 381 EVSKRPS 24 382 382 GAAGTCAGTAAGCGGCCCTCA 24 383 383 SSYAGSNSV 24 384 384 AGCTCATATGCAGGCAGCAACAGTGTC 25 385 385 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCGTATGGACTCACCTTCAGGGCCTA TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTCGAGTGGG TGGCAGTGTCATGGTATGACGGAACAAATGAAGTCTATGCAGACTCA GTGAAGGGCCGCTTCAGAATCTCCAGAGATGATTCCAGGAGCACTCT ATATTTGCAAATGAATAGTCTGAGAGGCGAGGACACGGCTGTATATT ACTGTGCGACAGAAAGGATGTGGGAGGAAAACTCCAGCAGCTTCGGC TGGTGGGGCCGGGGAACCCTGGTCACCGTCTCCTCA 25 386 386 QVQLVQSGGGVVQPGGSLRLSCAAYGLTFRAYGMHWVRQAPGKGLEW VAVSWYDGTNEVYADSVKGRFRISRDDSRSTLYLQMNSLRGEDTAVYY CATERMWEENSSSFGWWGRGTLVTVSS 25 387 387 LTFRAYGMH 25 388 388 CTCACCTTCAGGGCCTATGGCATGCAC 25 389 389 VSWYDGTNEVYADSVKG 25 390 390 GTGTCATGGTATGACGGAACAAATGAAGTCTATGCAGACTCAGTGAA GGGC 25 391 391 ATERMWEENSSSFGW 25 392 392 GCGACAGAAAGGATGTGGGAGGAAAACTCCAGCAGCTTCGGCTGG 25 393 393 CAGGCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATTTCCTGCACTGGAAGCAGCAGTGACGTTGGTGGTTCT AACTTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT CATGGTTTATGATGTCAATCATCGGCCCTCAGGGATTTCTAATCGCTT CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT CCAGGCTGAGGACGAGGCTGATTATTACTGCACCTCATATACAAGTA GAAGCTCTTATGTCTTCGGAAGTGGGACCAAGGTGACCGTACTT 25 394 394 QAVLTQPASVSGSPGQSITISCTGSSSDVGGSNFVSWYQQHPGKAPKLMV YDVNHRPSGISNRFSGSKSGNTASLTISGLQAEDEADYYCTSYTSRSSYVF GSGTKVTVL 25 395 395 TGSSSDVGGSNFVS 25 396 396 ACTGGAAGCAGCAGTGACGTTGGTGGTTCTAACTTTGTCTCC 25 397 397 DVNHRPS 25 398 398 GATGTCAATCATCGGCCCTCA 25 399 399 TSYTSRSSYV 25 400 400 ACCTCATATACAAGTAGAAGCTCTTATGTC 26 401 401 CAGGTCCAGCTGGTACAGTCTGGAACTGAAGTGAAGAAGCCTGGGGC CTCAGTGAAGGTCTCCTGTAAGGCCTCTGGGTACATCTTCGACCACTT TGCTATCACCTGGGTGCGCCAGGCCCCTGGACAAGGGCCTGAGTGGA TGGGATGGATCAGCGCTTATAATGGGAGAACAGAGGATTCAGGGAA ATTCCCGGGCAGACTCACCCTGACCACAGACCCCGCCACGCGGACAG CCTTCCTGGAACTGAGGGGCCTGACACCTGACGACACGGCCGTTTATT ACTGTGCGCGAGATGTCCCGGTCATGGGAGCCGCATTTTTGGACTACT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 26 402 402 QVQLVQSGTEVKKPGASVKVSCKASGYIFDHFAITWVRQAPGQGPEWM GWISAYNGRTEDSGKFPGRLTLTTDPATRTAFLELRGLTPDDTAVYYCA RDVPVMGAAFLDYWGQGTLVTVSS 26 403 403 YIFDHFAIT 26 404 404 TACATCTTCGACCACTTTGCTATCACC 26 405 405 WISAYNGRTEDSGKFPG 26 406 406 TGGATCAGCGCTTATAATGGGAGAACAGAGGATTCAGGGAAATTCCC GGGC 26 407 407 ARDVPVMGAAFLDY 26 408 408 GCGCGAGATGTCCCGGTCATGGGAGCCGCATTTTTGGACTAC 26 409 409 GAAATTGTATTGACACAGTCTCCACTCTCCCTGCCCGTCACTGTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTGGCCAAAGTCTCGAATTCAGT GATGGAAACACCTACTTGACTTGGTTTCACCAGAGGCCAGGCCAATC TCCAAGGCGCCTAATTTATAGGGGTTCTTACCGGGACTCTGGGGTCCC CGACAGATTCCGCGGCAGTGGCTCAGGCACTACTTTCACACTGACAA TCAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTTCTGCATGCAA GGTACACACTGGCCTCCGACCTTCGGCCAAGGGACCAAAGTGGATAT CAAA 26 410 410 EIVLTQSPLSLPVTVGQPASISCRSGQSLEFSDGNTYLTWFHQRPGQSPRR LIYRGSYRDSGVPDRFRGSGSGTTFTLTISRVEAEDVGIYFCMQGTHWPP TFGQGTKVDIK 26 411 411 RSGQSLEFSDGNTYLT 26 412 412 AGGTCTGGCCAAAGTCTCGAATTCAGTGATGGAAACACCTACTTGACT 26 413 413 RGSYRDS 26 414 414 AGGGGTTCTTACCGGGACTCT 26 415 415 MQGTHWPPT 26 416 416 ATGCAAGGTACACACTGGCCTCCGACC 27 417 417 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAAGTCTCCTGTGAGGCCTCTGCATACAGTTTCAGCGGCGA CTATGTTCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGTTGGATAAAGGCTGTCAATGGTGGCGCAAACTATGCACAGAGG TTTCACGGCAGGGTCACCATGACCACTGACTCGTCCAGGAGCACAGT CTATCTGGAGCTGACCAGGCTGACACCTGACGACACGGCCGTTTATTT TTGTGCGAAAGATCGAGCTGCAAGTGTTCATGTGCCAGCTGGTGAGT TTGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 27 418 418 QVQLVQSGAEVKKPGASVKVSCEASAYSFSGDYVHWVRQAPGQGLEW MGWIKAVNGGANYAQRFHGRVTMTTDSSRSTVYLELTRLTPDDTAVYF CAKDRAASVHVPAGEFDLWGQGTLVTVSS 27 419 419 YSFSGDYVH 27 420 420 TACAGTTTCAGCGGCGACTATGTTCAC 27 421 421 WIKAVNGGANYAQRFHG 27 422 422 TGGATAAAGGCTGTCAATGGTGGCGCAAACTATGCACAGAGGTTTCA CGGC 27 423 423 AKDRAASVHVPAGEFDL 27 424 424 GCGAAAGATCGAGCTGCAAGTGTTCATGTGCCAGCTGGTGAGTTTGA CCTC 27 425 425 GACATCCAGGTGACCCAGTCTCCTTCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCAGCATCACTTGTCGGGCAAGTCAGAGCATTAGCAACTT TTTAAATTGGTATCGGCAGAGACCAGGGAAAGCCCCTGAGCTCCTAA TCTATGCTGCCTCCACTTTGCAAGGTGGGGTCCCATCAAGGTTCAGTG GCAGTGGATCTGGGACACATTTCACTCTCACCATCAGCAGTCTCCAGC CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACACTATTCCTT CGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 27 426 426 DIQVTQSPSSLSASVGDRVSITCRASQSISNFLNWYRQRPGKAPELLIYAA STLQGGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQSYTIPSITFGQGT RLEIK 27 427 427 RASQSISNFLN 27 428 428 CGGGCAAGTCAGAGCATTAGCAACTTTTTAAAT 27 429 429 AASTLQG 27 430 430 GCTGCCTCCACTTTGCAAGGT 27 431 431 QQSYTIPSIT 27 432 432 CAACAGAGTTACACTATTCCTTCGATCACC 28 433 433 CAGGTGCAGCTGTTGGAGTCGGGCGCAGGACTTTTGAAGCCTTCGGA GACCCTGTCCCTCACCTGCTCTTTGTCTGGTGGGTCCTTCAGAGACTT CTACTGGGCCTGGATTCGCCAGGCCCCCGGGAGGGGGCTGGAGTGGA TTGGGGACATCAATGACGGTGGAAACACCAACCACAGTCCGTCCCTC AAGAGTCGAGCCATCCTTTCCATAGACGCGTCCAAGAGGCAGTTCTC CCTGAGACTGACCTCTGTGACCGCCGCGGACACGGCTGTTTATTATTG CGCGAGACAGAGGCTCGAACACACGGCATCTGGATATTACATGGACG TCTGGGGCAACGGGACCACGGTCACCGTCTCCTCA 28 434 434 QVQLLESGAGLLKPSETLSLTCSLSGGSFRDFYWAWIRQAPGRGLEWIG DINDGGNTNHSPSLKSRAILSIDASKRQFSLRLTSVTAADTAVYYCARQR LEHTASGYYMDVWGNGTTVTVSS 28 435 435 GSFRDFYWA 28 436 436 GGGTCCTTCAGAGACTTCTACTGGGCC 28 437 437 DINDGGNTNHSPSLKS 28 438 438 GACATCAATGACGGTGGAAACACCAACCACAGTCCGTCCCTCAAGAGT 28 439 439 ARQRLEHTASGYYMDV 28 440 440 GCGAGACAGAGGCTCGAACACACGGCATCTGGATATTACATGGACGTC 28 441 441 CAGTCTGTCCTGACGCAGCCGCCCTCGGTGTCAGTGGACCCAGGAGA GACGGCCACCATTACCTGTGGCGGAGCCAACATTGGTTCTAAAAATG TCTACTGGTATCAGCAGAGGCCAGGCCAGGCCCCTGTGCTGGTCGTCT ATGATGATATCGACCGGCCCGCAGGGATCCCTGATCGATTCACTGAC TCTAGTTCTGGGAACACGGTCACCCTGACCATCTACAGCGTCGAGGC CGTGGATGAGGCCGACTATTTCTGTCAGGTGTGGGATAATTCTTCTGA TCAGCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTC 28 442 442 QSVLTQPPSVSVDPGETATITCGGANIGSKNVYWYQQRPGQAPVLVVYD DIDRPAGIPDRFTDSSSGNTVTLTIYSVEAVDEADYFCQVWDNSSDQPVF GGGTKLTVL 28 443 443 GGANIGSKNVY 28 444 444 GGCGGAGCCAACATTGGTTCTAAAAATGTCTAC 28 445 445 DDIDRPA 28 446 446 GATGATATCGACCGGCCCGCA 28 447 447 QVWDNSSDQPV 28 448 448 CAGGTGTGGGATAATTCTTCTGATCAGCCGGTG 29 449 449 CAGGTCCAGCTTGTGCAGTCTGGAGCAGAGGCGAAAAAGCCCGGGG AGCCTCTGAGGATCTCCTGTAAGGGTTCTGGATACACCTTTAGCAGCT ACTGGATCAGCTGGGTGCGCCAGAGGCCCGGGGAACGCCTGGAGTGG ATGGGGAGAATTGATCCGAGTGACTCCTATGCCTACTCGAGCCCGTC CTTCCAAGGCCACGTCACCTTCTCAGCTGACAAGTCCAGCAACACTGC CTTTTTGCAGTGGAGCAGCCTGCAGGCCTCGGACACCGCCATCTATTA CTGCGCGAGACACAAAGAGAATTACGATTTTTGGGATTTCTGGGGCC AGGGCACAATGGTCACCGTCTCTTCA 29 450 450 QVQLVQSGAEAKKPGEPLRISCKGSGYTFSSYWISWVRQRPGERLEWMG RIDPSDSYAYSSPSFQGHVTFSADKSSNTAFLQWSSLQASDTAIYYCARH KENYDFWDFWGQGTMVTVSS 29 451 451 YTFSSYWIS 29 452 452 TACACCTTTAGCAGCTACTGGATCAGC 29 453 453 RIDPSDSYAYSSPSFQG 29 454 454 AGAATTGATCCGAGTGACTCCTATGCCTACTCGAGCCCGTCCTTCCAA GGC 29 455 455 ARHKENYDFWDF 29 456 456 GCGAGACACAAAGAGAATTACGATTTTTGGGATTTC 29 457 457 GAAACGACACTCACGCAGTCTCCAGACTCCCTGGCTGTGTCCCTGGG CGAGAGGGCCACCATCAACTGCAGGTCCAGCCAGCCTATTTTGTTCA ACCCCATCAATAAACTCTCCTTAGCTTGGTACCAGCTCAAACCAGGAC AGCCTCCTAAGCTGCTCATTTCCTGGGCATCTACCCGGGAACCCGGGG TCCCTGACCGATTCAATGGCAGCGGGTCTGGGACAGTTTTCACTCTCA CCATCAGCAGCCTGCAGCCTGAAGATGTGGCAGTTTATGTCTGTCAGC AATATTTTACTAGTACTTTTTTCGGCCCTGGGACCAAGGTGGAAATCA AA 29 458 458 ETTLTQSPDSLAVSLGERATINCRSSQPILFNPINKLSLAWYQLKPGQPPK LLISWASTREPGVPDRFNGSGSGTVFTLTISSLQPEDVAVYVCQQYFTSTF FGPGTKVEIK 29 459 459 RSSQPILFNPINKLSLA 29 460 460 AGGTCCAGCCAGCCTATTTTGTTCAACCCCATCAATAAACTCTCCTTA GCT 29 461 461 WASTREP 29 462 462 TGGGCATCTACCCGGGAACCC 29 463 463 QQYFTSTF 29 464 464 CAGCAATATTTTACTAGTACTTTT 30 465 465 GAGGTGCAGCTGTTGGAGTCTGGAAGTGAGGTGAAGAAGCCTGGGAC CTCAGTGAAGGTCTCCTGCGAGACTTCTGGTTACATCTTTACCAACTA TGCTATCTCCTGGGTGCGACAGGCCCCTGGACAGGGTCTTGAGTGGCT GGGTTGGATCAGTGGTTACAATGGTCAGACCTACTATGCGCAGAAGG TCCAGGGTAGACTCACCCTGACCACAGACACGTCCACGATGACAGCC TACATGGACCTGACGAGCCTTAGATCTGACGACACGGCCATTTATTAT TGTGTGAGAGATGTCCCCGTGATTTCAGGCGCTTCCACAATGGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 30 466 466 EVQLLESGSEVKKPGTSVKVSCETSGYIFTNYAISWVRQAPGQGLEWLG WISGYNGQTYYAQKVQGRLTLTTDTSTMTAYMDLTSLRSDDTAIYYCV RDVPVISGASTMDYWGQGTLVTVSS 30 467 467 YIFTNYAIS 30 468 468 TACATCTTTACCAACTATGCTATCTCC 30 469 469 WISGYNGQTYYAQKVQG 30 470 470 TGGATCAGTGGTTACAATGGTCAGACCTACTATGCGCAGAAGGTCCA GGGT 30 471 471 VRDVPVISGASTMDY 30 472 472 GTGAGAGATGTCCCCGTGATTTCAGGCGCTTCCACAATGGACTAC 30 473 473 GATATTGTGATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCATGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTTTACAGC GATGGAAACACCTACTTGAGTTGGTTTCAGCTGAGGCCAGGCCAATC TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA TCAGCCGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATGCAA GCTACACAGTGGCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAGAT CAAA 30 474 474 DIVMTQSPLSLPVTHGQPASISCRSSQSLVYSDGNTYLSWFQLRPGQSPRR LIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATQWP RTFGQGTKVEIK 30 475 475 RSSQSLVYSDGNTYLS 30 476 476 AGGTCTAGTCAAAGCCTCGTTTACAGCGATGGAAACACCTACTTGAGT 30 477 477 KVSNRDS 30 478 478 AAGGTTTCTAACCGGGACTCT 30 479 479 MQATQWPRT 30 480 480 ATGCAAGCTACACAGTGGCCTCGAACG 31 481 481 CAGGTCCAGCTTGTACAGTCTGGTCCTACGCTGGTGAGGCCCACACA GACCCTCACGCTGACTTGCACCTTCTCTGGGTTCTCACTCTCTACTCGT GGCGTGGGCGTGGGCTGGGTCCGTCAGTCCCCAGGAAAGGCCCCGGA GTTCCTTGTTCTCGCTCATTGGGATGATGATAAGATCTACAGTCCATC TCTCAGGCGCAGACTCTCCGTCACCAAGGATGTCTCCAAAAACCAGG TGGTCCTTGCCTTGACCAACGTGGACCCTGTGGACACAGGCACATATT TCTGTGTCAAGAGCGATCTCTATGATAGAGGTGGCTATTACTTATATT ACTTTGATCATTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA 31 482 482 QVQLVQSGPTLVRPTQTLTLTCTFSGFSLSTRGVGVGWVRQSPGKAPEFL VLAHWDDDKIYSPSLRRRLSVTKDVSKNQVVLALTNVDPVDTGTYFCV KSDLYDRGGYYLYYFDHWGQGTLVTVSS 31 483 483 FSLSTRGVGVG 31 484 484 TTCTCACTCTCTACTCGTGGCGTGGGCGTGGGC 31 485 485 LAHWDDDKIYSPSLRR 31 486 486 CTCGCTCATTGGGATGATGATAAGATCTACAGTCCATCTCTCAGGCGC 31 487 487 VKSDLYDRGGYYLYYFDH 31 488 488 GTCAAGAGCGATCTCTATGATAGAGGTGGCTATTACTTATATTACTTT GATCAT 31 489 489 GACATCCGGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTGCCAGTTA TGTGAATTGGTATCTGCAAAGACCAGGGGAAGCCCCTAAACTCCTGA TCTATGCAGCTTCCAATTTGCACAGTGGGGCCCCACCGTCACTCATTG GCAGGGGCTCTGGGACAGATTTCACTCTCACCATCAACACTCTGCAA CCTGAACATTTTGGAACTTACTTCTGTCAGCAGACTTTCTCCTCTCCAT ACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 31 490 490 DIRMTQSPSSLSASVGDRVTITCRASQTIASYVNWYLQRPGEAPKLLIYA ASNLHSGAPPSLIGRGSGTDFTLTINTLQPEHFGTYFCQQTFSSPYTFGQG TKVEIK 31 491 491 RASQTIASYVN 31 492 492 CGGGCAAGTCAGACCATTGCCAGTTATGTGAAT 31 493 493 AASNLHS 31 494 494 GCAGCTTCCAATTTGCACAGT 31 495 495 QQTFSSPYT 31 496 496 CAGCAGACTTTCTCCTCTCCATACACT 32 497 497 CAGGTGCAGCTGGTGGAGTCTGGTCCTACGCTGGTGAAGCCCACACA GACCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCACTCACTACTCG TGGCGTGGGTGTGGGCTGGGTCCGTCAGCCCCCAGGAAAGGCCCTGG AGTTCCTTGGACTCACTCATTGGGATGATGATAAGATCTACAGCCCAT CTCTCAGGCGCAGACTCACCATCACCAAGGACACCTCCAAAAACCAG GTGGTCCTTGCATTGGCCAACGTGGACCCTGTGGACACAGCCACATA TTTCTGTGTAAAAAGCGATCTCTATGATAGAGGTGGTTATTACTTATA CTACTTTGACTATTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA 32 498 498 QVQLVESGPTLVKPTQTLTLTCTFSGFSLTTRGVGVGWVRQPPGKALEFL GLTHWDDDKIYSPSLRRRLTITKDTSKNQVVLALANVDPVDTATYFCVK SDLYDRGGYYLYYFDYWGQGTLVTVSS 32 499 499 FSLTTRGVGVG 32 500 500 TTCTCACTCACTACTCGTGGCGTGGGTGTGGGC 32 501 501 LTHWDDDKIYSPSLRR 32 502 502 CTCACTCATTGGGATGATGATAAGATCTACAGCCCATCTCTCAGGCGC 32 503 503 VKSDLYDRGGYYLYYFDY 32 504 504 GTAAAAAGCGATCTCTATGATAGAGGTGGTTATTACTTATACTACTTT GACTAT 32 505 505 GAAATTGTGTTGACACAGTCTCCATCCTCCCTGTCTGCATCTGTGGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTCCCAGTTA TGTAAATTGGTATCTGCAAAGACCAGGGGAAGCCCCTAAACTCCTGA TCTATGGTGCTTCCAATTTGCACACTGGGGCCCCACCAACATTCATTG GCAGGGGATCTGGGGCAGATTTCACTCTCACCATCAACACTCTGCAA CCTGAACATTTTGGAACCTACTACTGTCAACAGACTTTCTCCTCTCCA TACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 32 506 506 EIVLTQSPSSLSASVGDRVTITCRASQTIPSYVNWYLQRPGEAPKLLIYGA SNLHTGAPPTFIGRGSGADFTLTINTLQPEHFGTYYCQQTFSSPYTFGQGT KVEIK 32 507 507 RASQTIPSYVN 32 508 508 CGGGCAAGTCAGACCATTCCCAGTTATGTAAAT 32 509 509 GASNLHT 32 510 510 GGTGCTTCCAATTTGCACACT 32 511 511 QQTFSSPYT 32 512 512 CAACAGACTTTCTCCTCTCCATACACT 33 513 513 CAGGTCACCTTGAAGGAGTCTGGTCCTGCGCTGGTGAAACCCACAGA GACCCTCACACTGACCTGTACCTTCTCTGGCTTCTCACTCAGCACTAA AAGACTGAGTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG AGTGGCTTGCTCGCATAGATTGGGATGATGATAAATCTTACAGCACA TCTCTGAGGACCAGGCTCACCATCGCCAAGGACACTTCCAAAAACCA GGTCGTCCTTACAATGACCAACATGGGCCCCGCGGACACAGCCACCT ATTTCTGTGTTCGGTCTTCTGTATATGCTAGTAATGCTTATTACCTCTA CTACTTTGACTCTTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 33 514 514 QVTLKESGPALVKPTETLTLTCTFSGFSLSTKRLSVSWIRQPPGKALEWL ARIDWDDDKSYSTSLRTRLTIAKDTSKNQVVLTMTNMGPADTATYFCV RSSVYASNAYYLYYFDSWGQGTLVTVSS 33 515 515 FSLSTKRLSVS 33 516 516 TTCTCACTCAGCACTAAAAGACTGAGTGTGAGT 33 517 517 RIDWDDDKSYSTSLRT 33 518 518 CGCATAGATTGGGATGATGATAAATCTTACAGCACATCTCTGAGGACC 33 519 519 VRSSVYASNAYYLYYFDS 33 520 520 GTTCGGTCTTCTGTATATGCTAGTAATGCTTATTACCTCTACTACTTTG ACTCT 33 521 521 GACATCCGGATGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTCGGA GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTGCCACCTA CTTAAATTGGTATCAGCACAAACCAGGGAAAGCCCCTACCCTCCTGA TCTATGCTGCATCCATTTTGCACAGTGGTGTCCCGCCAAGGTTCAGTG GCCGTGCCTCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC CTGAAGATTTTGCAACTTACTACTGTCAACAGGCCTACAGTTCCCCTT ACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 33 522 522 DIRMTQSPSSLSASVGDRVTITCRASQSIATYLNWYQHKPGKAPTLLIYA ASILHSGVPPRFSGRASGTDFTLTISSLQPEDFATYYCQQAYSSPYTFGQG TKVDIK 33 523 523 RASQSIATYLN 33 524 524 CGGGCAAGTCAGAGCATTGCCACCTACTTAAAT 33 525 525 AASILHS 33 526 526 GCTGCATCCATTTTGCACAGT 33 527 527 QQAYSSPYT 33 528 528 CAACAGGCCTACAGTTCCCCTTACACT 34 529 529 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCGGCAGCT ATGCTGTCATCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGG ATGGGACATATCATCCCTGTTTTTGGGACAATAAACAACGCACAGAA GTTCCAGGGCAGACTCACCCTTAGCGCAGACGAATCCACGGGCACAG TCTACATGGGGCTGAGCAGCCTGAGATCTGACGACACGGCCGTGTAT TTCTGTGCGACCAAGAGATATTGTAGTGATCCCAGCTGCCATGGACTC TGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCCTCA 34 530 530 QVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYAVIWVRQAPGQGLEW MGHIIPVFGTINNAQKFQGRLTLSADESTGTVYMGLSSLRSDDTAVYFCA TKRYCSDPSCHGLWYFDLWGRGTLVTVSS 34 531 531 GTFGSYAVI 34 532 532 GGCACCTTCGGCAGCTATGCTGTCATC 34 533 533 HIIPVFGTINNAQKFQG 34 534 534 CATATCATCCCTGTTTTTGGGACAATAAACAACGCACAGAAGTTCCA GGGC 34 535 535 ATKRYCSDPSCHGLWYFDL 34 536 536 GCGACCAAGAGATATTGTAGTGATCCCAGCTGCCATGGACTCTGGTA CTTCGATCTC 34 537 537 GACATCCGGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCTTGGATAGT GATGATGGAAACACCTATTTGGACTGGTACCTGCAGAAGCCAGGGCA GTCTCCACAGGTCCTGATCTATATGCTTTCGTATCGGGCCTCTGGAGT CCCAGACAGGTTCAGTGGCAGTGGGTCAGGCACTGATTTCACACTGA AAATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATG CAACGTGCAGAGTTTCCTTACACTTTTGGCCAGGGGACCAAGCTGGA GATCAAA 34 538 538 DIRLTQSPLSLPVTPGEPASISCRSSQSLLDSDDGNTYLDWYLQKPGQSPQ VLIYMLSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRAEF PYTFGQGTKLEIK 34 539 539 RSSQSLLDSDDGNTYLD 34 540 540 AGGTCTAGTCAGAGCCTCTTGGATAGTGATGATGGAAACACCTATTT GGAC 34 541 541 MLSYRAS 34 542 542 ATGCTTTCGTATCGGGCCTCT 34 543 543 MQRAEFPYT 34 544 544 ATGCAACGTGCAGAGTTTCCTTACACT 35 545 545 CAGGTCCAGCTTGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGA GCCTCTGAGGATCTCCTGTAAGGGTTCTGGATACACCTTTACCAGCTA CTGGATCAGTTGGGTGCGCCAGATGCCCGGGACAGGCCTTGAGTGGA TGGGGAGAATTGATCCGAGTGACTCCTATACCTACTCGAGCCCGTCCT TCCAAGGCCACGTCACCATCTCAGTTGACAAGTCCATCAGCACTGCCT ACCTGCAATGGAGCAGCCTGAAGGCCTCGGACACCGCCATATATTAC TGTGCGAGACACAAAGAGAATTACGATTTTTGGGATTTTTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 35 546 546 QVQLVQSGAEVKKPGEPLRISCKGSGYTFTSYWISWVRQMPGTGLEWM GRIDPSDSYTYSSPSFQGHVTISVDKSISTAYLQWSSLKASDTAIYYCARH KENYDFWDFWGQGTLVTVSS 35 547 547 YTFTSYWIS 35 548 548 TACACCTTTACCAGCTACTGGATCAGT 35 549 549 RIDPSDSYTYSSPSFQG 35 550 550 AGAATTGATCCGAGTGACTCCTATACCTACTCGAGCCCGTCCTTCCAA GGC 35 551 551 ARHKENYDFWDF 35 552 552 GCGAGACACAAAGAGAATTACGATTTTTGGGATTTT 35 553 553 GAAACGACACTCACGCAGTCTCCAGACTCCCTGGCTGTGTCCCTGGG CGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGACTATTTTCTTCA ACTCCAATAATAAGATCTCCTTAGCTTGGTACCAGCAGAAACCAGGA CAGCCTCCTAAGCTGCTCATTTCCTGGGCATCTACCCGCGAATCCGGG GTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTC ACCATCAGCAGCCTGCAGCCTGAGGATGTGGCAGTTTATTTCTGTCAG CAATATTATAGTAGTGCTTTTTTCGGCCCTGGGACACGACTGGAGATT AAA 35 554 554 ETTLTQSPDSLAVSLGERATINCKSSQTIFFNSNNKISLAWYQQKPGQPPK LLISWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDVAVYFCQQYYSSAF FGPGTRLEIK 35 555 555 KSSQTIFFNSNNKISLA 35 556 556 AAGTCCAGCCAGACTATTTTCTTCAACTCCAATAATAAGATCTCCTTA GCT 35 557 557 WASTRES 35 558 558 TGGGCATCTACCCGCGAATCC 35 559 559 QQYYSSAF 35 560 560 CAGCAATATTATAGTAGTGCTTTT 36 561 561 CAGGTCCAGCTGGTGCAGTCTGGACCTGAAGTGAAGAAGCCTGGGGC CTCAGTGACGATCTCCTGTCAGGCCTCTGGGTACATCTTCAATCACTA CTCTATCACCTGGGTGCGACAGGCCCCTGGACAAGGGACTGAGTGGA TGGGGTGGATCAGCGCCTATCACGGTAAGACGGAATATTCAGGGAAA TTCCACGGCAGAGTCACCCTGACCACAGACACAGGCACGCGGACAGC CTTCTTGGAACTTAGGGACCTGACATCTGACGACACGGCCATTTATTA TTGTGCGCGAGATGTCCCGGTCATGGGAGCCGCATTTTTGGACTACTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 36 562 562 QVQLVQSGPEVKKPGASVTISCQASGYIFNHYSITWVRQAPGQGTEWMG WISAYHGKTEYSGKFHGRVTLTTDTGTRTAFLELRDLTSDDTAIYYCAR DVPVMGAAFLDYWGQGTLVTVSS 36 563 563 YIFNHYSIT 36 564 564 TACATCTTCAATCACTACTCTATCACC 36 565 565 WISAYHGKTEYSGKFHG 36 566 566 TGGATCAGCGCCTATCACGGTAAGACGGAATATTCAGGGAAATTCCA CGGC 36 567 567 ARDVPVMGAAFLDY 36 568 568 GCGCGAGATGTCCCGGTCATGGGAGCCGCATTTTTGGACTAC 36 569 569 GAAATTGTGTTGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTGGTCAAAGTCTCGAATTCAGT GATGGAAACACCTACTTGACTTGGTTTCAGCAGAGGCCAGGCCAATC TCCAAGGCGCCTAATTTTTAGGGGTTCTTACCGGGACTCTGGGGTCCC CGAAAGATTCAGCGGCAGTGGCTCAGGCACTTCTTTCACACTGACAA TCAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTTCTGCATGCAA GGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGCTGGAGAT CAAA 36 570 570 EIVLTQSPLSLPVTLGQPASISCRSGQSLEFSDGNTYLTWFQQRPGQSPRR LIFRGSYRDSGVPERFSGSGSGTSFTLTISRVEAEDVGIYFCMQGTHWPPT FGQGTKLEIK 36 571 571 RSGQSLEFSDGNTYLT 36 572 572 AGGTCTGGTCAAAGTCTCGAATTCAGTGATGGAAACACCTACTTGACT 36 573 573 RGSYRDS 36 574 574 AGGGGTTCTTACCGGGACTCT 36 575 575 MQGTHWPPT 36 576 576 ATGCAAGGTACACACTGGCCTCCGACG 37 577 577 CAGGTGCAGCTGGTGCAGTCTGGCCCTGCGCTGGTGAAACCCACGCA GACCCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCACCACTGC AAGAATGTGTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG AGTGGCTTGCACGCATTGATTGGGATGATGATAAATCCTACAGCACA TCTCTGAAGACCAGGCTCACCATCGCCAAGGACACATCCAAAAACCA GGTCGTCCTTACCATGACCAACATGGGCCCCGCGGACACAGCCACTT ATTACTGTGTACGGACTCCTATATATGCTAGTGGTGGTTATTACCTCT CCTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 37 578 578 QVQLVQSGPALVKPTQTLTLTCTFSGFSLTTARMCVSWIRQPPGKALEW LARIDWDDDKSYSTSLKTRLTIAKDTSKNQVVLTMTNMGPADTATYYC VRTPIYASGGYYLSYFDSWGQGTLVTVSS 37 579 579 FSLTTARMCVS 37 580 580 TTCTCACTCACCACTGCAAGAATGTGTGTGAGT 37 581 581 RIDWDDDKSYSTSLKT 37 582 582 CGCATTGATTGGGATGATGATAAATCCTACAGCACATCTCTGAAGACC 37 583 583 VRTPIYASGGYYLSYFDS 37 584 584 GTACGGACTCCTATATATGCTAGTGGTGGTTATTACCTCTCCTACTTT GACTCC 37 585 585 GATATTGTGATGACGCAGTCTCCATCCTCCCTGTCTGCATCTGTCGGA GACAGCGTCACCATCACTTGCCGGGCAAGTCAGACTATTGCCAGCTA TGTGAATTGGTATCAGCACAAACCAGGGCAAGCCCCTAACCTCCTGA TCTATGCTGCATCCATTTTGCACAGTGGGGTCCCATCAAGGTTCAGAG GCGGTGGCTCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAAC CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTT ACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 37 586 586 DIVMTQSPSSLSASVGDSVTITCRASQTIASYVNWYQHKPGQAPNLLIYA ASILHSGVPSRFRGGGSGTDFTLTINSLQPEDFATYYCQQSYSTPYTFGQG TKVDIK 37 587 587 RASQTIASYVN 37 588 588 CGGGCAAGTCAGACTATTGCCAGCTATGTGAAT 37 589 589 AASILHS 37 590 590 GCTGCATCCATTTTGCACAGT 37 591 591 QQSYSTPYT 37 592 592 CAACAGAGTTACAGTACCCCTTACACT 38 593 593 CAGGTGCAGCTGGTGGAGTCTGGTCCTACGCTGGTGAAACCCACACA GACCCTCTCGCTGACCTGCACCTTCTCTGGGTTCTCACTCACCACTCG TGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGG AGTGGCTTGGATTCACTTATTGGGATGGTGATGACCGCTACAGCCCAT CTCTGAGGAACAGAGTCTCCATCGCCAAGGACACCTCCAAAAACCAG GTGGTCCTTACACTGACCAACATGGACCCTGTGGACACAGCCACGTA TTTTTGTGTACACAGCGATCGCTATGACAGGGGTGGTTATTACTTATA CTTCTTTGACTACTGGGGCCCGGGAACCCTGGTCACCGTCTCCTCA 38 594 594 QVQLVESGPTLVKPTQTLSLTCTFSGFSLTTRGVGVGWIRQPPGKALEWL GFTYWDGDDRYSPSLRNRVSIAKDTSKNQVVLTLTNMDPVDTATYFCV HSDRYDRGGYYLYFFDYWGPGTLVTVSS 38 595 595 FSLTTRGVGVG 38 596 596 TTCTCACTCACCACTCGTGGAGTGGGTGTGGGC 38 597 597 FTYWDGDDRYSPSLRN 38 598 598 TTCACTTATTGGGATGGTGATGACCGCTACAGCCCATCTCTGAGGAAC 38 599 599 VHSDRYDRGGYYLYFFDY 38 600 600 GTACACAGCGATCGCTATGACAGGGGTGGTTATTACTTATACTTCTTT GACTAC 38 601 601 GACATCCGAGTCACCCAGTCTCCATCCTCCCTGTCTGCGTCTGTGGGG GACAGAGTCTCCATCAGTTGCCGGGCAAGTCAGACCATTGCCAGTTA TGTAAATTGGTATCAGCAGAGACCAGGGAAAGCCCCTCAACTCCTGA TCTTTGCTGCATCCCATTTGCAGACTGGGGTCCCATCAAGATTCAGTG GCAGGGGCTCTGGGACAGATTTCACTCTCACCATCACCTCTCTGCAAC CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACACTTCCCCGT ACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 38 602 602 DIRVTQSPSSLSASVGDRVSISCRASQTIASYVNWYQQRPGKAPQLLIFAA SHLQTGVPSRFSGRGSGTDFTLTITSLQPEDFATYYCQQSYTSPYTFGQGT KVEIK 38 603 603 RASQTIASYVN 38 604 604 CGGGCAAGTCAGACCATTGCCAGTTATGTAAAT 38 605 605 AASHLQT 38 606 606 GCTGCATCCCATTTGCAGACT 38 607 607 QQSYTSPYT 38 608 608 CAACAGAGTTACACTTCCCCGTACACT 39 609 609 GAGGTGCAGCTGGTGGAGTCTGGTCCTACGCTGGTGAAACCCACACA GACCCTCACGCTGACCTGCTCCCTCTCTGGGTTCTCACTCACCACTCG TGGGGTGGGTGTGGGCTGGATCCGCCAGCCCCCAGGAAAGGCCCCGG AGTGCCTTGGATTCGTTTATTGGGATGATGATAACCGCTACAGCCCAT CTCTGAGGGGCAGACTCACCATCTCCAAGGACACGTCCAAGAACCAG GTGGTCCTTACACTGACCAACATGGACCCTTTGGACACAGCCACCTAT TACTGTGTTCACAGCGATCTCTATGATAGAGGTGGTTATTACTTATTC TACTTTGACGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 39 610 610 EVQLVESGPTLVKPTQTLTLTCSLSGFSLTTRGVGVGWIRQPPGKAPECL GFVYWDDDNRYSPSLRGRLTISKDTSKNQVVLTLTNMDPLDTATYYCV HSDLYDRGGYYLFYFDDWGQGTLVTVSS 39 611 611 FSLTTRGVGVG 39 612 612 TTCTCACTCACCACTCGTGGGGTGGGTGTGGGC 39 613 613 FVYWDDDNRYSPSLRG 39 614 614 TTCGTTTATTGGGATGATGATAACCGCTACAGCCCATCTCTGAGGGGC 39 615 615 VHSDLYDRGGYYLFYFDD 39 616 616 GTTCACAGCGATCTCTATGATAGAGGTGGTTATTACTTATTCTACTTT GACGAC 39 617 617 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGCCCATTGCCAGTTA TTTAAATTGGTATCAGCAGAAACCAGGGCAAGCCCCTAAACTCCTCA TCTATGCTGCATCCATGTTGCAGAGTGGGGCCCCATCAAAATTCAGTG GCCGGGGATCTGGGACAGATTTCACTCTCACCATCACCACTCTACAAC CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACACTTTCCCGT ACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 39 618 618 DIQVTQSPSSLSASVGDRVTITCRASQPIASYLNWYQQKPGQAPKLLIYA ASMLQSGAPSKFSGRGSGTDFTLTITTLQPEDFATYYCQQSYTFPYTFGQ GTKVEIK 39 619 619 RASQPIASYLN 39 620 620 CGGGCAAGTCAGCCCATTGCCAGTTATTTAAAT 39 621 621 AASMLQS 39 622 622 GCTGCATCCATGTTGCAGAGT 39 623 623 QQSYTFPYT 39 624 624 CAACAGAGTTACACTTTCCCGTACACT 40 625 625 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTA CTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGG TTTCATATATTAGTATTAGTAGTAGTTACACAGACTACGCAGACTCTG TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTA CTGTGCGAGAGATCAACGAGACCAAGCAGTGGCTGGTCGGTGGTTCG ACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 40 626 626 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVS YISISSSYTDYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD QRDQAVAGRWFDPWGQGTLVTVSS 40 627 627 FTFSDYYMS 40 628 628 TTCACCTTCAGTGACTACTACATGAGC 40 629 629 YISISSSYTDYADSVKG 40 630 630 TATATTAGTATTAGTAGTAGTTACACAGACTACGCAGACTCTGTGAAG GGC 40 631 631 ARDQRDQAVAGRWFDP 40 632 632 GCGAGAGATCAACGAGACCAAGCAGTGGCTGGTCGGTGGTTCGACCCC 40 633 633 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG GTTTTGATGTACACTGGTACCAGCAGGTTCCAGGAACAGCCCCCAAA CTCCTCATCTATGCTAACACCAATCGGCCCTCAGGGGTCCCAGACCGA TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG CTCAAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAA CAGCCTGAGTGGTTCGGCGGTCTTCGGCGGAGGGACCAAGGTCACCG TCCTA 40 634 634 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGFDVHWYQQVPGTAPKLLI YANTNRPSGVPDRFSGSKSGTSASLAITGLKAEDEADYYCQSYDNSLSGS AVFGGGTKVTVL 40 635 635 TGSSSNIGAGFDVH 40 636 636 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTTTGATGTACAC 40 637 637 ANTNRPS 40 638 638 GCTAACACCAATCGGCCCTCA 40 639 639 QSYDNSLSGSAV 40 640 640 CAGTCCTATGACAACAGCCTGAGTGGTTCGGCGGTC 41 641 641 CAGGTGCAGCTGGTGCAATCTGGTTCTGAGGTGAAGCAGCCTGGGGC CTCAGTGAAGGTCTCCTGCAAGGCCTCTGGATACACCTTCAGCGCCTA CCATCTGCACTGGGTGCGCCAGGCCCCCGGACAAGGGCTTCAGTGGC TGGGCAGGATCAACCCTAACAGTGGTGCCACAAGCGTTGCACATAAC TTTCAGGGCAGGGTCACCTTGACCACGGACACGTCCATCAGCACAGC CTACATGGAGCTGAGCAGCCTGACGTCTGACGACAGTGCCGTGTATT ACTGCGCGAGAACTATGTGGCGGTGGCTGGTCGAGGGGGGCTTTGAG AACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 41 642 642 QVQLVQSGSEVKQPGASVKVSCKASGYTFSAYHLHWVRQAPGQGLQW LGRINPNSGATSVAHNFQGRVTLTTDTSISTAYMELSSLTSDDSAVYYCA RTMWRWLVEGGFENWGQGTLVTVSS 41 643 643 YTFSAYHLH 41 644 644 TACACCTTCAGCGCCTACCATCTGCAC 41 645 645 RINPNSGATSVAHNFQG 41 646 646 AGGATCAACCCTAACAGTGGTGCCACAAGCGTTGCACATAACTTTCA GGGC 41 647 647 ARTMWRWLVEGGFEN 41 648 648 GCGAGAACTATGTGGCGGTGGCTGGTCGAGGGGGGCTTTGAGAAC 41 649 649 GACATCCGGATGACCCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGT AATGGAGACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTC TCCACAGGTCCTGATCTATCTGGGTTCTAATCGGGCCTCCGGGGTCCC TGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA GCTCTACAAACTCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAAT CAAA 41 650 650 DIRMTQSPLSLPVTPGEPASISCRSSQSLLHSNGDNYLDWYLQKPGQSPQ VLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTP LTFGGGTKVEIK 41 651 651 RSSQSLLHSNGDNYLD 41 652 652 AGGTCTAGTCAGAGCCTCCTGCATAGTAATGGAGACAACTATTTGGAT 41 653 653 LGSNRAS 41 654 654 CTGGGTTCTAATCGGGCCTCC 41 655 655 MQALQTPLT 41 656 656 ATGCAAGCTCTACAAACTCCGCTCACT 42 657 657 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCGGGGTC CTCGATGAGCATCTCCTGTCGGGCTTCTGGAGGCTCCTTCAACAACCA AGCTATACACTGGATCCGCCAGGCCCCTGGAGAAGGACTTGAGTGGA TGGGAAATATCATCCCTAATTTCGGATCTCAAAACTACGCGCCGGAA TTCGTGGGCAGGGTCAGCTTCAATGCGGACGCTTCCGCTGGCACTGCC TACATGGACTTGAGTGATCTGACATCTCAAGACACGGCCGTCTATTAC TGTGCGACAGCCGGGTGGTTCGGGGAATTGGTGCGCTTTGACTCCTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 42 658 658 QVQLVQSGAEVKKPGSSMSISCRASGGSFNNQAIHWIRQAPGEGLEWMG NIIPNFGSQNYAPEFVGRVSFNADASAGTAYMDLSDLTSQDTAVYYCAT AGWFGELVRFDSWGQGTLVTVSS 42 659 659 GSFNNQAIH 42 660 660 GGCTCCTTCAACAACCAAGCTATACAC 42 661 661 NIIPNFGSQNYAPEFVG 42 662 662 AATATCATCCCTAATTTCGGATCTCAAAACTACGCGCCGGAATTCGTG GGC 42 663 663 ATAGWFGELVRFDS 42 664 664 GCGACAGCCGGGTGGTTCGGGGAATTGGTGCGCTTTGACTCC 42 665 665 GATATTGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG GGAAGGGCCACCCTCTCCTGCAGGGCCAGTGAGACTATTACCACTAA CTTAGCCTGGTACCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCCTCA TCTATGGTGCGTCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG GCAGTGGGTCAGGGACAGAGTTCACTCTCACCATCAACAGCCTGCAG TCTGAGGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCT CCTCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA 42 666 666 DIVMTQSPATLSVSPGGRATLSCRASETITTNLAWYQQKPGQAPRLLIYG ASTRATGIPARFSGSGSGTEFTLTINSLQSEDFAVYYCQQYNNWPPLTFG GGTKLEIK 42 667 667 RASETITTNLA 42 668 668 AGGGCCAGTGAGACTATTACCACTAACTTAGCC 42 669 669 GASTRAT 42 670 670 GGTGCGTCCACCAGGGCCACT 42 671 671 QQYNNWPPLT 42 672 672 CAGCAGTATAATAACTGGCCTCCTCTCACT 43 673 673 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGGTGAAGCCTTCGGA GACCCTGTCCCTCACCTGCGCTGTGTCTGGTGGGTCCTTCAGGGGTTA CCAGTGGAACTGGTTCCGCCAGCCCCCCGGGAAGGGTCTGGAGTGGA TTGGGGAAATCAATCATGGTGAATACACCCACTACAACGCGTCCCTC AAGAGTCGCGTCAGTTTATCTATAGACACGTCCAAGAACCAGTTCTCC CTTAATCTGACCTCTGTGACCGCCGCGGACACGGCTATGTATTTTTGT GCGAGAGCCTCGAGTGGGACCTATAACTTCGAGTACTGGTTCGACCC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 43 674 674 QVQLQQWGAGLVKPSETLSLTCAVSGGSFRGYQWNWFRQPPGKGLEWI GEINHGEYTHYNASLKSRVSLSIDTSKNQFSLNLTSVTAADTAMYFCARA SSGTYNFEYWFDPWGQGTLVTVSS 43 675 675 GSFRGYQWN 43 676 676 GGGTCCTTCAGGGGTTACCAGTGGAAC 43 677 677 EINHGEYTHYNASLKS 43 678 678 GAAATCAATCATGGTGAATACACCCACTACAACGCGTCCCTCAAGAGT 43 679 679 ARASSGTYNFEYWFDP 43 680 680 GCGAGAGCCTCGAGTGGGACCTATAACTTCGAGTACTGGTTCGACCCC 43 681 681 TCCTATGTGCTGACACAGCCACCCTCGGTGTCAGTGGCCCCAGGAAA GACGGCCTGGCTTACCTGTGGGGGAAACAACATTGGAAATAAAAGAG TGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTG TATGATGATTACGGCCGGCCCTCAGGGACCTCTGAGCGAGTCTCTGG CTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAG CCGGGGATGAGGCCGAGTATTATTGTCAGGTGTGGGATGATCCCAGT GATCATGCGGTGTTCGGCGGAGGCACCCAGCTGACCGTCCTC 43 682 682 SYVLTQPPSVSVAPGKTAWLTCGGNNIGNKRVHWYQQKPGQAPVLVVY DDYGRPSGTSERVSGSNSGNTATLTISRVEAGDEAEYYCQVWDDPSDHA VFGGGTQLTVL 43 683 683 GGNNIGNKRVH 43 684 684 GGGGGAAACAACATTGGAAATAAAAGAGTGCAC 43 685 685 DDYGRPS 43 686 686 GATGATTACGGCCGGCCCTCA 43 687 687 QVWDDPSDHAV 43 688 688 CAGGTGTGGGATGATCCCAGTGATCATGCGGTG 44 689 689 CAGGTCCAGCTGGTGCAGTCTGGGGGACGACTGGTCAAGCCTGGGGG GTCCCTGAGACTCTCCTGTGGAATGTCTGGATTCGGCTTCAGTAGTTA TAGAATGAATTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGA TCTCATCGATTAGTGCTAGTAGTAGTTATACAGACTACGCGAATTCAG TGAAGGGCCGATTCACCATCTCCAGAGACGGCGCCAATTTGTTTCTGC AAATGAACAGCCTGAGAGTCGAGGACACGGCTGTGTATTATTGTGCG AGAGATTGGGGGGGACATTCCATTTTTGGAGCGGTCCAAGACCTCTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 44 690 690 QVQLVQSGGRLVKPGGSLRLSCGMSGFGFSSYRMNWVRQAPGKGLEWI SSISASSSYTDYANSVKGRFTISRDGANLFLQMNSLRVEDTAVYYCARD WGGHSIFGAVQDLWGQGTLVTVSS 44 691 691 FGFSSYRMN 44 692 692 TTCGGCTTCAGTAGTTATAGAATGAAT 44 693 693 SISASSSYTDYANSVKG 44 694 694 TCGATTAGTGCTAGTAGTAGTTATACAGACTACGCGAATTCAGTGAA GGGC 44 695 695 ARDWGGHSIFGAVQDL 44 696 696 GCGAGAGATTGGGGGGGACATTCCATTTTTGGAGCGGTCCAAGACCTC 44 697 697 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCTGGGCA GAGGGTCACCATCTCCTGCTCTGGGAGCAGTTCCAACATCGGGGCAG GTTATGATGTCCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA CTCCTCATCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGACCGA TTCTCTGGCTCCAAGTCTGGCACGTCAGCCTCCCTGGCCATCACTGGC CTCCAGGCCGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAG AAGCCTGAGTCAGGTCTTCGGAGCTGGGACCAAGGTGACCGTCCTA 44 698 698 QSVLTQPPSVSGAPGQRVTISCSGSSSNIGAGYDVHWYQQLPGTAPKLLI YGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSQV FGAGTKVTVL 44 699 699 SGSSSNIGAGYDVH 44 700 700 TCTGGGAGCAGTTCCAACATCGGGGCAGGTTATGATGTCCAC 44 701 701 GNTNRPS 44 702 702 GGTAACACCAATCGGCCCTCA 44 703 703 QSYDRSLSQV 44 704 704 CAGTCCTATGACAGAAGCCTGAGTCAGGTC 45 705 705 CAGGTCACCTTGAAGGAGTCTGGTCCTGCGCTGGTGAGACCCAAACA GACCCTCACTCTGACCTGCTCCTTCTCCGGCTTCTCACTCGACACTCA AAGAACGGGTGTGAATTGGATCCGTCAGTCCCCAGGGAAGGCCCTGG AGTGGCTTGCACGGATTGATTGGGATGGCAATATTTACTCCAGCACCT CTGTGAGGACCAAACTCAGCATCTCCAAGGGCACCTCCAAAAACCAG GTGGTCCTTACAATGACCGACGTGGACCCTGTGGACACAGCCACCTA TTACTGTGCACGGACTCTTTACTATACTTCTGGTGGTTATTACTTGAAC CTCTTTGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA 45 706 706 QVTLKESGPALVRPKQTLTLTCSFSGFSLDTQRTGVNWIRQSPGKALEWL ARIDWDGNIYSSTSVRTKLSISKGTSKNQVVLTMTDVDPVDTATYYCAR TLYYTSGGYYLNLFDYWGQGTLVTVSS 45 707 707 FSLDTQRTGVN 45 708 708 TTCTCACTCGACACTCAAAGAACGGGTGTGAAT 45 709 709 RIDWDGNIYSSTSVRT 45 710 710 CGGATTGATTGGGATGGCAATATTTACTCCAGCACCTCTGTGAGGACC 45 711 711 ARTLYYTSGGYYLNLFDY 45 712 712 GCACGGACTCTTTACTATACTTCTGGTGGTTATTACTTGAACCTCTTTG ACTAC 45 713 713 GAAATTGTGATGACGCAGTCTCCACCCTCCCTGTCTGCCTCTGTTGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGACAATTCCCAGCTA TGTCAATTGGTATCAGCAGATATCAGGGAAAGCCCCTCGCCTCCTGAT CTATGCTGCCTCACTTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGG CAGCGGATCTGGGACAGAGTTCAGTCTCACCATCAGCGGTCTGCGAC CTGAGGATTTTGGCACTTACTACTGTCAACAGAGTTACAGTTCCACTC CCACTTTCGGCCAGGGGACACGACTGGAGATTAAA 45 714 714 EIVMTQSPPSLSASVGDRVTITCRASQTIPSYVNWYQQISGKAPRLLIYAA SLLQSGVPSRFSGSGSGTEFSLTISGLRPEDFGTYYCQQSYSSTPTFGQGTR LEIK 45 715 715 RASQTIPSYVN 45 716 716 CGGGCAAGTCAGACAATTCCCAGCTATGTCAAT 45 717 717 AASLLQS 45 718 718 GCTGCCTCACTTTTGCAAAGT 45 719 719 QQSYSSTPT 45 720 720 CAACAGAGTTACAGTTCCACTCCCACT 46 721 721 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTC CTCGGTGAAGGTCTCCTGTAAGGTTGTCGGAGGCAGTTTCAGCAACT ATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTAT CTGGGAGGGATCATCCCCGCCTTTAGGACAGCAAAATATGCAAAGAA ATTCCAGGACAGACTCACAATTACCGCGGACGAATCTACGAGCACTG CCTACATGGAAATGAGGGGCCTGACATCTGACGACACGGGCCTATAT TATTGTGCGAGGCCTGAAGGAGACTTTGGGGATTTGAAGTGGCTACG ATCGCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 46 722 722 EVQLVESGAEVKRPGSSVKVSCKVVGGSFSNYAISWVRQAPGQGPEYLG GIIPAFRTAKYAKKFQDRLTITADESTSTAYMEMRGLTSDDTGLYYCARP EGDFGDLKWLRSPFDYWGQGTLVTVSS 46 723 723 GSFSNYAIS 46 724 724 GGCAGTTTCAGCAACTATGCTATCAGC 46 725 725 GIIPAFRTAKYAKKFQD 46 726 726 GGGATCATCCCCGCCTTTAGGACAGCAAAATATGCAAAGAAATTCCA GGAC 46 727 727 ARPEGDFGDLKWLRSPFDY 46 728 728 GCGAGGCCTGAAGGAGACTTTGGGGATTTGAAGTGGCTACGATCGCC CTTTGACTAC 46 729 729 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG CAAAGAGTCACCCTTTCCTGCAGGGCCAGTCAGGGTGTGAGCATCAA CTTAGCCTGGTACCAGCAGAAACCTGGCCAGCCTCCCAGGCTCCTCAT CTATGGTGCATCCACCCGGGCCACTGATATCCCAGCCAGGTTCAGTG GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAG TCTGAAGATTTTGCAGTTTATTATTGTCAGCAGTATGATGACTGGCCT CCCCAGCTCACTTTCGGCCCTGGGACCAAGCTGGAGATCAAA 46 730 730 EIVLTQSPATLSVSPGQRVTLSCRASQGVSINLAWYQQKPGQPPRLLIYG ASTRATDIPARFSGSGSGTDFTLTISSLQSEDFAVYYCQQYDDWPPQLTF GPGTKLEIK 46 731 731 RASQGVSINLA 46 732 732 AGGGCCAGTCAGGGTGTGAGCATCAACTTAGCC 46 733 733 GASTRAT 46 734 734 GGTGCATCCACCCGGGCCACT 46 735 735 QQYDDWPPQLT 46 736 736 CAGCAGTATGATGACTGGCCTCCCCAGCTCACT 47 737 737 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTAGTGAAGCCTTCGGA GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAATAACTA CTTCTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGC TTGGATATATCTACAACAGTGGGAGCACCTACTACAACCCCTCCCTCA ACAGTCGAGTCACCATCTCATTACAAAAGTCCAAGAACCAGTTCTCC CTGCACCTGACGTCCATGACCGCCGCCGATACGGCCGTGTATTTCTGT GCGAGACATCCAAGTGTGATCTACGGGACTTTCGGCGCCAACGGGGG GCCAAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 47 738 738 QVQLQESGPGLVKPSETLSLTCTVSGGSINNYFWSWIRQPPGKGLEWLG YIYNSGSTYYNPSLNSRVTISLQKSKNQFSLHLTSMTAADTAVYFCARHP SVIYGTFGANGGPNWFDPWGQGTLVTVSS 47 739 739 GSINNYFWS 47 740 740 GGCTCCATCAATAACTACTTCTGGAGC 47 741 741 YIYNSGSTYYNPSLNS 47 742 742 TATATCTACAACAGTGGGAGCACCTACTACAACCCCTCCCTCAACAGT 47 743 743 ARHPSVIYGTFGANGGPNWFDP 47 744 744 GCGAGACATCCAAGTGTGATCTACGGGACTTTCGGCGCCAACGGGGG GCCAAACTGGTTCGACCCC 47 745 745 CAGTCTGTTCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTATGTCTCCTGGTACCAACAACACCCAGGCAAGGCCCCCAAACT CATGATTTTCGATGTCACTTATCGGCCCTCAGGGATTTCTAATCGCTT CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT CCACTCTGAGGACGAGGCTGATTATTATTGCAGCTCATATACAGGCA GCAACACCGTGATTTTCGGCGGAGGGACCAAGCTGACCGTCCTA 47 746 746 QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMI FDVTYRPSGISNRFSGSKSGNTASLTISGLHSEDEADYYCSSYTGSNTVIF GGGTKLTVL 47 747 747 TGTSSDVGGYNYVS 47 748 748 ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCC 47 749 749 DVTYRPS 47 750 750 GATGTCACTTATCGGCCCTCA 47 751 751 SSYTGSNTVI 47 752 752 AGCTCATATACAGGCAGCAACACCGTGATT 48 753 753 CAGGTCCAGCTTGTACAGTCTGGGGCTGAAGTGAAGAAGCCTGGGGC CTCAGTGAGGGTCTCCTGCAAGGCTTCTGGCTACACCTTCAGCAGCTA CTATATTCACTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTGGC TGGGATGGATCAACCCAAAGAGTGGTGACACAATCTATTCATATAAG TTTCAGGGCAGGGTCACCTTGACCAGGGAAACGTCAATCACCACAGC CTACATGGAGTTGACCAGTCTGAGATCTGACGACACGGCCGTCTATT ACTGTGCGCGAGTTACTTGGCAGTGGCTGGTCCTGGGGGGTTTTGACT ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 48 754 754 QVQLVQSGAEVKKPGASVRVSCKASGYTFSSYYIHWVRQAPGQGPEWL GWINPKSGDTIYSYKFQGRVTLTRETSITTAYMELTSLRSDDTAVYYCAR VTWQWLVLGGFDYWGQGTLVTVSS 48 755 755 YTFSSYYIH 48 756 756 TACACCTTCAGCAGCTACTATATTCAC 48 757 757 WINPKSGDTIYSYKFQG 48 758 758 TGGATCAACCCAAAGAGTGGTGACACAATCTATTCATATAAGTTTCA GGGC 48 759 759 ARVTWQWLVLGGFDY 48 760 760 GCGCGAGTTACTTGGCAGTGGCTGGTCCTGGGGGGTTTTGACTAC 48 761 761 GATATTGTGCTGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCTGAGCCTCCTGCATAGT AATGGAGACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTC TCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCC TGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA TCAGCCGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA GCTCTACACACTCCCCTCACTTTCGGCGGAGGGACCAAGCTGGAGAT CAAA 48 762 762 DIVLTQSPLSLPVTPGEPASISCRSSLSLLHSNGDNYLDWYLQKPGQSPQL LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALHTPL TFGGGTKLEIK 48 763 763 RSSLSLLHSNGDNYLD 48 764 764 AGGTCTAGTCTGAGCCTCCTGCATAGTAATGGAGACAACTATTTGGAT 48 765 765 LGSNRAS 48 766 766 TTGGGTTCTAATCGGGCCTCC 48 767 767 MQALHTPLT 48 768 768 ATGCAAGCTCTACACACTCCCCTCACT 49 769 769 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAAACTCTCCTGTACTTCCTCTGGGCTCGCCTTCAGTGGCTCT GCTATACACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGT TGGCCGTATTAGAAGCAAACCTAACAGTTACGCGACAGAATATGCTG CGTCGGTGAAGGGGAGGTTCACCATCTCCAGAGATGATTCACAGAAC ACGGCGTATCTGCAAATGAACAGCCTGAAAGCCGAGGACACGGCCCT GTATTACTGTACTTTAGGATATTGTAGTGGTGATAGCTGCTCCTCTCTT AGGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 49 770 770 EVQLVESGGGLVQPGGSLKLSCTSSGLAFSGSAIHWVRQASGKGLEWVG RIRSKPNSYATEYAASVKGRFTISRDDSQNTAYLQMNSLKAEDTALYYC TLGYCSGDSCSSLRDYWGQGTLVTVSS 49 771 771 LAFSGSAIH 49 772 772 CTCGCCTTCAGTGGCTCTGCTATACAC 49 773 773 RIRSKPNSYATEYAASVKG 49 774 774 CGTATTAGAAGCAAACCTAACAGTTACGCGACAGAATATGCTGCGTC GGTGAAGGGG 49 775 775 TLGYCSGDSCSSLRDY 49 776 776 ACTTTAGGATATTGTAGTGGTGATAGCTGCTCCTCTCTTAGGGACTAC 49 777 777 CAGTCTGCTCTGATTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTATGTCTCTTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT CATGATTTATGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGTA GCAGCACTCTCGTGTTCGGCGGAGGGACCAAGGTCACCGTCCTA 49 778 778 QSALIQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMI YDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLVF GGGTKVTVL 49 779 779 TGTSSDVGGYNYVS 49 780 780 ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCT 49 781 781 DVSNRPS 49 782 782 GATGTCAGTAATCGGCCCTCA 49 783 783 SSYTSSSTLV 49 784 784 AGCTCATATACAAGTAGCAGCACTCTCGTG 50 785 785 CAGGTCCAGCTGGTGCAGTCTGGAAGTGAGGTGAAGAAGCCTGGGGC CTCGGTGAAGGTCTCCTGCAAGGCCTCAGGTTACAGGTTTTCCAACTA TGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGCCTAGAGTGGA TGGGATGGATCAGCGCTTACAATGGAAACATAAAGTATGGAAATAAC CTCCAGGGCAGAGTCACCGTGACCACAGACACATCCACGACCACGGC CTACATGGAGGTGAGGAGCCTGACATCTGACGACACGGCCGTGTATT ACTGTGCGAGAGATGTCCCAGCTGACGGGGTCCACTTCATGGACGTC TGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 50 786 786 QVQLVQSGSEVKKPGASVKVSCKASGYRFSNYGISWVRQAPGQGLEWM GWISAYNGNIKYGNNLQGRVTVTTDTSTTTAYMEVRSLTSDDTAVYYC ARDVPADGVHFMDVWGKGTTVTVSS 50 787 787 YRFSNYGIS 50 788 788 TACAGGTTTTCCAACTATGGTATCAGC 50 789 789 WISAYNGNIKYGNNLQG 50 790 790 TGGATCAGCGCTTACAATGGAAACATAAAGTATGGAAATAACCTCCA GGGC 50 791 791 ARDVPADGVHFMDV 50 792 792 GCGAGAGATGTCCCAGCTGACGGGGTCCACTTCATGGACGTC 50 793 793 GATATTGTGATGACTCAGACTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTACACAGT GATACTAACACCTACTTGAACTGGTTTCAGCAGAGGCCAGGCCAATC TCCACGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTACTTTCACACTGAAAA TCAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCAG GGTTCACACTGGGCTCCGACTTTCGGCCAGGGGACCAAGGTGGAAAT CAAA 50 794 794 DIVMTQTPLSLPVTLGQPASISCRSSQSLVHSDTNTYLNWFQQRPGQSPR RLIYKVSNRDSGVPDRFSGSGSGTTFTLKISRVEAEDVGIYYCMQGSHWA PTFGQGTKVEIK 50 795 795 RSSQSLVHSDTNTYLN 50 796 796 AGGTCTAGTCAAAGCCTCGTACACAGTGATACTAACACCTACTTGAAC 50 797 797 KVSNRDS 50 798 798 AAGGTTTCTAACCGGGACTCT 50 799 799 MQGSHWAPT 50 800 800 ATGCAGGGTTCACACTGGGCTCCGACT 51 801 801 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAACTA TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG TGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCC GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGGT ATATCTGCAAATGAACAGCCTGAGAGCCGACGACACGGCTGTCTATT ACTGTGCGAGAGATGCGATATTTGGCAGTGGCCCCAACTGGTTCGAC CCCTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA 51 802 802 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEW VAVIWYDGSNKYYADSVKGRFTISRDNSKNTVYLQMNSLRADDTAVYY CARDAIFGSGPNWFDPWGQGTLVTVSS 51 803 803 FTFSNYGMH 51 804 804 TTCACCTTCAGTAACTATGGCATGCAC 51 805 805 VIWYDGSNKYYADSVKG 51 806 806 GTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAA GGGC 51 807 807 ARDAIFGSGPNWFDP 51 808 808 GCGAGAGATGCGATATTTGGCAGTGGCCCCAACTGGTTCGACCCC 51 809 809 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA CTCCTCATCTATGGTAGCAGCAATCGGCCCTCAGGGGTCCCTGACCGG TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGAAAG CAGCCTGAGAGGTTGGGTGTTCGGCGGAGGGACCAAGGTCACCGTCC TA 51 810 810 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLI YGSSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYESSLRGW VFGGGTKVTVL 51 811 811 TGSSSNIGAGYDVH 51 812 812 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 51 813 813 GSSNRPS 51 814 814 GGTAGCAGCAATCGGCCCTCA 51 815 815 QSYESSLRGWV 51 816 816 CAGTCCTATGAAAGCAGCCTGAGAGGTTGGGTG 52 817 817 GAGGTGCAGCTGGTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGA GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACC ATGCTATGTACTGGGTCCGCCAGGCTCCAGGCAAAGGGCTAGAGTGG GTGGCACTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCC GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT GTATCTGCAGATGAACAGCCTGAGAGCTGAGGACACGGCTGTCTATT ACTGTGCGAGAGATCAATGGCTGGTTCCTGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 52 818 818 EVQLVESGGGVVQPGRSLRLSCAASGFTFSDHAMYWVRQAPGKGLEW VALISFDGRNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDQWLVPDYWGQGTLVTVSS 52 819 819 FTFSDHAMY 52 820 820 TTCACCTTCAGTGACCATGCTATGTAC 52 821 821 LISFDGRNIYYADSVKG 52 822 822 CTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCCGTGAA GGGC 52 823 823 ARDQWLVPDY 52 824 824 GCGAGAGATCAATGGCTGGTTCCTGACTAC 52 825 825 CAGTCTGTTCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTATGTCTCCTGGTACCAACAGCACCCAGGCAACGCCCCCAAACT CATGATTTATGAAGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT CTCTGGCTTCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA GCAACAGTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA 52 826 826 QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGNAPKLMI YEVSKRPSGVPDRFSGFKSGNTASLTVSGLQAEDEADYYCSSYAGSNSV FGTGTKVTVL 52 827 827 TGTSSDVGGYNYVS 52 828 828 ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCC 52 829 829 EVSKRPS 52 830 830 GAAGTCAGTAAGCGGCCCTCA 52 831 831 SSYAGSNSV 52 832 832 AGCTCATATGCAGGCAGCAACAGTGTC 53 833 833 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAGGCCGGGGG GGTCCCTTGGACTCTCATGTTCAGCCTCTGGATTCATTTTCAGTAACG CTTGGATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGG GTCGGCCATATTAAAAGCAAAGTTAATGGTGGGACAACAGCCTACGG TGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCACGAA ACACGCTGTTTCTGCAAATGAACAGCCTGAAAACCGAGGACACAGGC GTGTATTACTGTACTACAGGCCCACCCTATCAGTACTTTGATGATTCC GGTTATTCGGTCGTGGACTACTGGGGCCAGGGAACCCTGGTCACCGT CTCCTCC 53 834 834 EVQLVESGGGLVRPGGSLGLSCSASGFIFSNAWMTWVRQAPGKGLEWV GHIKSKVNGGTTAYGAPVKGRFTISRDDSRNTLFLQMNSLKTEDTGVYY CTTGPPYQYFDDSGYSVVDYWGQGTLVTVSS 53 835 835 FIFSNAWMT 53 836 836 TTCATTTTCAGTAACGCTTGGATGACC 53 837 837 HIKSKVNGGTTAYGAPVKG 53 838 838 CATATTAAAAGCAAAGTTAATGGTGGGACAACAGCCTACGGTGCACC CGTGAAAGGC 53 839 839 TTGPPYQYFDDSGYSVVDY 53 840 840 ACTACAGGCCCACCCTATCAGTACTTTGATGATTCCGGTTATTCGGTC GTGGACTAC 53 841 841 CAGTCTGTGGTGACGCAGCCGCCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGGAAGCGACTCCAACATCGGAACTG ATTATTTTTACTGGTACCAGCAGCTCCCAGGATCGGCCCCCAAACTCC TCATCTATGGTAGTAATCAGCGGCCCTCCGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCTCCGCAGCCTCCCTGGCCATCAGTGGCCTCC GGTCCGAGGATGACGCTGACTATTACTGTGCAGCATGGGATGACAGC CTGGGTGGTCCGGTGTTCGGCGGTGGGACCAAGGTCACCGTCCTA 53 842 842 QSVVTQPPSASGTPGQRVTISCSGSDSNIGTDYFYWYQQLPGSAPKLLIY GSNQRPSGVPDRFSGSQSGSAASLAISGLRSEDDADYYCAAWDDSLGGP VFGGGTKVTVL 53 843 843 SGSDSNIGTDYFY 53 844 844 TCTGGAAGCGACTCCAACATCGGAACTGATTATTTTTAC 53 845 845 GSNQRPS 53 846 846 GGTAGTAATCAGCGGCCCTCC 53 847 847 AAWDDSLGGPV 53 848 848 GCAGCATGGGATGACAGCCTGGGTGGTCCGGTG 54 849 849 CAGGTGCAGCTACAGCAGTGGGGCACAGGACTGGTGAAGCCTTCGGA GACCCTGTCCCTAACCTGCGCAGTCTCTGGTGGGGCCTTCAGCGGTCA CCAGTGGAACTGGTTCCGCCAGCCCCCCGGGAAGGGTCTGGAGTGGA TTGGAGAAATCAATGTCAGTGGCAACACCCACTACAACGTGTCCCTC AGGAGTCGGGTCACCATTTCTCTGGACGAGTCCAAGAAACAATTCTC CCTGAAAATGACCTCTGTCACCGCCGCGGATACGGCTATTTACTACTG TGCGAAAGCCTCGAGTGGGTCTTATCACTTCGAGTATTGGTTCGACCC CTGGAGCCAGGGAACAATGGTCACCGTCTCCTCA 54 850 850 QVQLQQWGTGLVKPSETLSLTCAVSGGAFSGHQWNWFRQPPGKGLEWI GEINVSGNTHYNVSLRSRVTISLDESKKQFSLKMTSVTAADTAIYYCAKA SSGSYHFEYWFDPWSQGTMVTVSS 54 851 851 GAFSGHQWN 54 852 852 GGGGCCTTCAGCGGTCACCAGTGGAAC 54 853 853 EINVSGNTHYNVSLRS 54 854 854 GAAATCAATGTCAGTGGCAACACCCACTACAACGTGTCCCTCAGGAGT 54 855 855 AKASSGSYHFEYWFDP 54 856 856 GCGAAAGCCTCGAGTGGGTCTTATCACTTCGAGTATTGGTTCGACCCC 54 857 857 TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGGCCCCAGGAAA GATGGCCTGGTTTACCTGTGGGGGAAGCGACATTGGAAGTAAAAGAG TCCACTGGTACCAGCAGAAGCCGGGCCAGGCCCCTGTCCTGCTCGTG TATGATGATTCCTTACGTCCCTCAGGGACCTCTGCCCGAGTCTCTGGC TCCACCTCTGGCAACACGGCCACCCTGAGTATCATCAGCGTCGAAGC CGGGGATGAGGCCGACTATTTTTGTCAGGTGTGGGATGATGCCGACG ATCATGCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 54 858 858 SYELTQPPSVSVAPGKMAWFTCGGSDIGSKRVHWYQQKPGQAPVLLVY DDSLRPSGTSARVSGSTSGNTATLSIISVEAGDEADYFCQVWDDADDHA VFGGGTKLTVL 54 859 859 GGSDIGSKRVH 54 860 860 GGGGGAAGCGACATTGGAAGTAAAAGAGTCCAC 54 861 861 DDSLRPS 54 862 862 GATGATTCCTTACGTCCCTCA 54 863 863 QVWDDADDHAV 54 864 864 CAGGTGTGGGATGATGCCGACGATCATGCGGTG 55 865 865 GAGGTGCAGCTGGTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGA GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACC ATGCTATGTACTGGGTCCGCCAGGCTCCAGGCAAAGGGCTAGAGTGG GTGGCACTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCC GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT GTATCTGCAGATGAACAGCCTGAGAGCTGAGGACACGGCTGTCTATT ACTGTGCGAGAGATCAATGGCTGGTTCCTGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 55 866 866 EVQLVESGGGVVQPGRSLRLSCAASGFTFSDHAMYWVRQAPGKGLEW VALISFDGRNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDQWLVPDYWGQGTLVTVSS 55 867 867 FTFSDHAMY 55 868 868 TTCACCTTCAGTGACCATGCTATGTAC 55 869 869 LISFDGRNIYYADSVKG 55 870 870 CTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCCGTGAA GGGC 55 871 871 ARDQWLVPDY 55 872 872 GCGAGAGATCAATGGCTGGTTCCTGACTAC 55 873 873 CAGTCTGCTCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTATGTCTCCTGGTACCAACAGCACCCAGGCAACGCCCCCAAACT CATGATTTATGAAGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT CTCTGGCTTCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA GCAACAGTGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 55 874 874 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGNAPKLMI YEVSKRPSGVPDRFSGFKSGNTASLTVSGLQAEDEADYYCSSYAGSNSV FGTGTKVTVL 55 875 875 TGTSSDVGGYNYVS 55 876 876 ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCC 55 877 877 EVSKRPS 55 878 878 GAAGTCAGTAAGCGGCCCTCA 55 879 879 SSYAGSNSV 55 880 880 AGCTCATATGCAGGCAGCAACAGTGTC 56 881 881 CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACA GACCCTCACGCTGACCTGCTCCTTCTCTGGGTTCTCACTCACCACTCG TGGAGTGGGTGTGGGCTGGGTCCGTCAGCCCCCAGGAAAGGCCCTGG AGTGCCTTGGATTCGTTTATTGGGACGATGATAAGCGCTACAGCCCAT CTCTGAGGAGCAGACTCACCATCTCCGAGGACACGTCCAAAAACCAG GTGGTCCTTACAATGACCAACATGGACCCTTTGGACACAGCCACGTA TTACTGTGTACACAGCGATCTCTATGATAGAGGTGGTTATTACTTATT CTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 56 882 882 QITLKESGPTLVKPTQTLTLTCSFSGFSLTTRGVGVGWVRQPPGKALECL GFVYWDDDKRYSPSLRSRLTISEDTSKNQVVLTMTNMDPLDTATYYCV HSDLYDRGGYYLFYFDYWGQGTLVTVSS 56 883 883 FSLTTRGVGVG 56 884 884 TTCTCACTCACCACTCGTGGAGTGGGTGTGGGC 56 885 885 FVYWDDDKRYSPSLRS 56 886 886 TTCGTTTATTGGGACGATGATAAGCGCTACAGCCCATCTCTGAGGAGC 56 887 887 VHSDLYDRGGYYLFYFDY 56 888 888 GTACACAGCGATCTCTATGATAGAGGTGGTTATTACTTATTCTACTTT GACTAC 56 889 889 GATATTGTGCTGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGCCCATTGCCAGCTA TTTAAATTGGTATCAGCACAAACCAGGGAAAGCCCCTAAACTCCTGA TCTATGCTGCATCCAGTTTGCAGAGTGGGGTCTCATCAACATTCAGTG GCCGGGGATCTGGGACAGATTTCACTCTCACCATCACCGCTCTGCAAC CTGAAGATTTTGCAATTTACTACTGTCAACAGAGTTACACTTTCCCGT ACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 56 890 890 DIVLTQSPSSLSASVGDRVTITCRASQPIASYLNWYQHKPGKAPKLLIYAA SSLQSGVSSTFSGRGSGTDFTLTITALQPEDFAIYYCQQSYTFPYTFGQGT KVDIK 56 891 891 RASQPIASYLN 56 892 892 CGGGCAAGTCAGCCCATTGCCAGCTATTTAAAT 56 893 893 AASSLQS 56 894 894 GCTGCATCCAGTTTGCAGAGT 56 895 895 QQSYTFPYT 56 896 896 CAACAGAGTTACACTTTCCCGTACACT 57 897 897 CAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAGCCGGGGG AGTCTCTGAAGATCTCCTGTCAAGGTTCTGGATATAGTTTTAGAAGTT ACTGGATCGGTTGGGTGCGCCAGAAGCCCGGGAAAGGCCTGGAATAT ATGGGCATCATCTTTCCTAATGACTTTGATACCAGATACAGCCCGTCC TTCCAAGGCCAGGTCACCATCTCCGTCGACAAGTCCACCAGCACCGC CTTCCTGCAGTGGACCAGCCTGCAGGCCTCGGACACCGCCATATATTA TTGTGGCAGACAAGAGCTGCAGGGTAGTTTTACTATATGGGGCCAAG GGACAATGGTCACCGTCACTTCA 57 898 898 QVQLVQSGAEVKKPGESLKISCQGSGYSFRSYWIGWVRQKPGKGLEYM GIIFPNDFDTRYSPSFQGQVTISVDKSTSTAFLQWTSLQASDTAIYYCGRQ ELQGSFTIWGQGTMVTVTS 57 899 899 YSFRSYWIG 57 900 900 TATAGTTTTAGAAGTTACTGGATCGGT 57 901 901 IIFPNDFDTRYSPSFQG 57 902 902 ATCATCTTTCCTAATGACTTTGATACCAGATACAGCCCGTCCTTCCAA GGC 57 903 903 GRQELQGSFTI 57 904 904 GGCAGACAAGAGCTGCAGGGTAGTTTTACTATA 57 905 905 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCCGCATCTGTCGGA GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATGGGCAATTC TTTAAATTGGTATCAGCAAAAGTCAGGGAAAGCCCCTAAACTCCTGA TCTACGATGCATCGTATTTGGATTCAGGGGTCCCATCAAGGTTCAGTG GCAGTGGATCTGGGACACATTTTACTTTCACCATCAGCACCCTGCAGC CTGAAGATATTGCAACATATTACTGTCAACATTATGATAATCTCCTCT TATTCACTTTCGGCCCTGGGACCAAGCTGGAGATCAAA 57 906 906 DIVMTQSPSSLSASVGDRVTITCQASQDMGNSLNWYQQKSGKAPKLLIY DASYLDSGVPSRFSGSGSGTHFTFTISTLQPEDIATYYCQHYDNLLLFTFG PGTKLEIK 57 907 907 QASQDMGNSLN 57 908 908 CAGGCGAGTCAGGACATGGGCAATTCTTTAAAT 57 909 909 DASYLDS 57 910 910 GATGCATCGTATTTGGATTCA 57 911 911 QHYDNLLLFT 57 912 912 CAACATTATGATAATCTCCTCTTATTCACT 58 913 913 CAGATCACCTTGAAGGAGTCTGGTCCTACCCTGGTGAAACCCACACA GACCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCACTCACCACTCG TGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGG AGTTCCTAGGATTCATTCATTGGGATGATGATAAGACCTACAGCCCAT CTCTGAGGAGGAGACTCACCATCACCAAGGACACCTCCAACAACGAG GTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATA TTACTGTGTCCACAGCGATCTCTATGATAGTGGTGGTTATTACTTATA CTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 58 914 914 QITLKESGPTLVKPTQTLTLTCTFSGFSLTTRGVGVGWIRQPPGKALEFLG FIHWDDDKTYSPSLRRRLTITKDTSNNEVVLTMTNMDPVDTATYYCVHS DLYDSGGYYLYYFDYWGQGTLVTVSS 58 915 915 FSLTTRGVGVG 58 916 916 TTCTCACTCACCACTCGTGGAGTGGGTGTGGGC 58 917 917 FIHWDDDKTYSPSLRR 58 918 918 TTCATTCATTGGGATGATGATAAGACCTACAGCCCATCTCTGAGGAGG 58 919 919 VHSDLYDSGGYYLYYFDY 58 920 920 GTCCACAGCGATCTCTATGATAGTGGTGGTTATTACTTATACTACTTT GACTAC 58 921 921 GAAATTGTGATGACACAGTCTCCATCCTCCCTGTCTGCATCTGTGGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGCCCATTCCCAGTTA TGTAAATTGGTATCAGCAGAGACCAGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAATTTGCAGAGTGGGGTCTCATCAAAATTTAGTG GCAGGGGATTTGGGACAGATTTCACTCTCACCATCGACACTCTGCAA CCTGAAGATTTTGCAACTTACTACTGTCAACAGGTTTACACTTCCCCG TACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 58 922 922 EIVMTQSPSSLSASVGDRVTITCRASQPIPSYVNWYQQRPGKAPKLLIYA ASNLQSGVSSKFSGRGFGTDFTLTIDTLQPEDFATYYCQQVYTSPYTFGQ GTKLEIK 58 923 923 RASQPIPSYVN 58 924 924 CGGGCAAGTCAGCCCATTCCCAGTTATGTAAAT 58 925 925 AASNLQS 58 926 926 GCTGCATCCAATTTGCAGAGT 58 927 927 QQVYTSPYT 58 928 928 CAACAGGTTTACACTTCCCCGTACACT 59 929 929 GAGGTGCAGCTGGTGGAGTCTGGTCCTACGCTGGTGAAGCCCACACA GACCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCACTCACCACTCG TGGAATGGGTGTGGGCTGGATCCGTCAGCCCCCAGGCAGGTCCCTGG AATGGCTTGCAGTCATTTATTGGGATGGTGATGTGCGCTACAGTCCAT CTCTGAAGGGCAGGCTCACCATCACCAAAGACACCCCCAAAAACCAG GTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATA TTACTGTGTACACAGCGATCTCTATGATAGGAATGCTTATTACCTGCA CTACTTTGACTTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA 59 930 930 EVQLVESGPTLVKPTQTLTLTCTFSGFSLTTRGMGVGWIRQPPGRSLEWL AVIYWDGDVRYSPSLKGRLTITKDTPKNQVVLTMTNMDPVDTATYYCV HSDLYDRNAYYLHYFDFWGQGTLVTVSS 59 931 931 FSLTTRGMGVG 59 932 932 TTCTCACTCACCACTCGTGGAATGGGTGTGGGC 59 933 933 VIYWDGDVRYSPSLKG 59 934 934 GTCATTTATTGGGATGGTGATGTGCGCTACAGTCCATCTCTGAAGGGC 59 935 935 VHSDLYDRNAYYLHYFDF 59 936 936 GTACACAGCGATCTCTATGATAGGAATGCTTATTACCTGCACTACTTT GACTTC 59 937 937 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCGGGCAAGTCAGATTATTGCCAGTTA TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGA TCTTTGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCCGTG GCAGTGGATCTGGGACAGATTTCACTCTCACCATAAGCAGTCTGCAA CCTGAAGACTTTGCAACTTACTACTGTCAACAGAGTTACAGTATACCG TACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 59 938 938 DIRLTQSPSSLSASVGDRVTITCRASQIIASYLNWYQQKPGKAPNLLIFAA SSLQSGVPSRFRGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPYTFGQGT KLEIK 59 939 939 RASQIIASYLN 59 940 940 CGGGCAAGTCAGATTATTGCCAGTTATTTAAAT 59 941 941 AASSLQS 59 942 942 GCTGCATCCAGTTTGCAAAGT 59 943 943 QQSYSIPYT 59 944 944 CAACAGAGTTACAGTATACCGTACACT 60 945 945 CAGGTCCAGCTGGTGCAGTCTGGTCCTGCACTGGTGAAACCCACACA GACCCTCACGCTGACCTGCACCTTCTCTGGATTCTCACTCACCACTCG TGGAGTGGGTGTGGGCTGGATCCGTCAGACCCCAGGAAAGGCCCTGG AGTGCCTTGGATTCATTTATTGGGATGATGATATGAACTACAACCCAT CTCTGAGGGGCAGAGTCACCATCACCAGGGACACCTCCAAAAACCAG GTGGTCCTAACAATGACCAACATGGCCCCTGTGGACACAGGCACATA TTACTGTGTACACAGCGATCTCTATGATAGTAGCGGTTATTATTTATA TTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 60 946 946 QVQLVQSGPALVKPTQTLTLTCTFSGFSLTTRGVGVGWIRQTPGKALECL GFIYWDDDMNYNPSLRGRVTITRDTSKNQVVLTMTNMAPVDTGTYYCV HSDLYDSSGYYLYYFDYWGQGTLVTVSS 60 947 947 FSLTTRGVGVG 60 948 948 TTCTCACTCACCACTCGTGGAGTGGGTGTGGGC 60 949 949 FIYWDDDMNYNPSLRG 60 950 950 TTCATTTATTGGGATGATGATATGAACTACAACCCATCTCTGAGGGGC 60 951 951 VHSDLYDSSGYYLYYFDY 60 952 952 GTACACAGCGATCTCTATGATAGTAGCGGTTATTATTTATATTACTTT GACTAC 60 953 953 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGG GACAGAGTCACCATCACTTGCCGGGCAAGTCAGCCCATTGCCAGTTA TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGA TCTATGCTGCATCCAATTTGCAGAGTGGGGTCCCTTCAACATTCAGTG GCAGGGGATCTGGGACAGATTTCTCTCTCACCATCTCCACTCTGCAAC CTGAAGACATTGCAACTTACTACTGTCAACAGAGTTACACCTCCCCCT ACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 60 954 954 DIRLTQSPSSLSASVGDRVTITCRASQPIASYLNWYQQKPGKAPKLLIYAA SNLQSGVPSTFSGRGSGTDFSLTISTLQPEDIATYYCQQSYTSPYTFGQGT KVEIK 60 955 955 RASQPIASYLN 60 956 956 CGGGCAAGTCAGCCCATTGCCAGTTATTTAAAT 60 957 957 AASNLQS 60 958 958 GCTGCATCCAATTTGCAGAGT 60 959 959 QQSYTSPYT 60 960 960 CAACAGAGTTACACCTCCCCCTACACT 61 961 961 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTTAAGCCGGGGGG GTCCCTTAGACTCTCATGTGCAGCCTCTGGATTCATTTTCAATAACGC CTGGATGACCTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGG TTGGCCGTATAAAAACCAATGCTGATGGTGGGACTGCAGACTACAGT ACACCCGTGAAAGGCAGATTCGCCATCTCAAGAGATGATTCTACAAA CACGCTGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCG TCTATTACTGTACCACAGGCCCACCCTATAAGTACTCTGACAGTACTG GTTATTCGGTCGTTGACTACTGGGGCCAGGGCACCCTGGTCACTGTCT CTTCA 61 962 962 EVQLLESGGGLVKPGGSLRLSCAASGFIFNNAWMTWVRQAPGRGLEWV GRIKTNADGGTADYSTPVKGRFAISRDDSTNTLYLQMNSLKTEDTAVYY CTTGPPYKYSDSTGYSVVDYWGQGTLVTVSS 61 963 963 FIFNNAWMT 61 964 964 TTCATTTTCAATAACGCCTGGATGACC 61 965 965 RIKTNADGGTADYSTPVKG 61 966 966 CGTATAAAAACCAATGCTGATGGTGGGACTGCAGACTACAGTACACC CGTGAAAGGC 61 967 967 TTGPPYKYSDSTGYSVVDY 61 968 968 ACCACAGGCCCACCCTATAAGTACTCTGACAGTACTGGTTATTCGGTC GTTGACTAC 61 969 969 TCCTATGAGCTGACGCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTA ATTATGTATATTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC CTCATCTATAGTACTAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC TCTGGCTCCCAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC CGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCGTGGGATGACCG CCTGAGTGGTCCGGTGTTCGGCGGGGGCACCCAGCTGACCGTCCTC 61 970 970 SYELTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYS TNQRPSGVPDRFSGSQSGTSASLAISGLRSEDEADYYCAAWDDRLSGPVF GGGTQLTVL 61 971 971 SGSSSNIGSNYVY 61 972 972 TCTGGAAGCAGCTCCAACATCGGAAGTAATTATGTATAT 61 973 973 STNQRPS 61 974 974 AGTACTAATCAGCGGCCCTCA 61 975 975 AAWDDRLSGPV 61 976 976 GCAGCGTGGGATGACCGCCTGAGTGGTCCGGTG 62 977 977 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCGGGGTC CTCGGTGAAAATCTCCTGTAAGGCTTCTGGAGGCACCTTCAAAAGTC AAGCTATTCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGG ATGGGAAACATCATCCCTACCTACGGATCACCAAACTTCGCGCAGAG GTTCCTCGGCAGGGTCACCTTCATTGCGGACGATTCCACTGGCGCTGC CTCCATGGACCTGTATAGGCTGACATCTGAGGACACGGCCGTCTATTA CTGTGCGACAGCCGGGTGGTTCGGAGAATTAGTGCGGTTTGACTCCT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 62 978 978 QVQLVQSGAEVKKPGSSVKISCKASGGTFKSQAIHWVRQAPGQGLEWM GNIIPTYGSPNFAQRFLGRVTFIADDSTGAASMDLYRLTSEDTAVYYCAT AGWFGELVRFDSWGQGTLVTVSS 62 979 979 GTFKSQAIH 62 980 980 GGCACCTTCAAAAGTCAAGCTATTCAC 62 981 981 NIIPTYGSPNFAQRFLG 62 982 982 AACATCATCCCTACCTACGGATCACCAAACTTCGCGCAGAGGTTCCTC GGC 62 983 983 ATAGWFGELVRFDS 62 984 984 GCGACAGCCGGGTGGTTCGGAGAATTAGTGCGGTTTGACTCC 62 985 985 GATATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCACTGAGAGTATTAGCAGCAA CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG GCAGTGGGTCAGGGACAGAGTTCACTCTCACCATCAACAGCCTGCAG TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCT CCTCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 62 986 986 DIVMTQSPATLSVSPGERATLSCRATESISSNLAWYQQKPGQAPRLLIYG ASTRATGIPARFSGSGSGTEFTLTINSLQSEDFAVYYCQQYNNWPPLTFG GGTKVDIK 62 987 987 RATESISSNLA 62 988 988 AGGGCCACTGAGAGTATTAGCAGCAACTTAGCC 62 989 989 GASTRAT 62 990 990 GGTGCATCCACCAGGGCCACT 62 991 991 QQYNNWPPLT 62 992 992 CAGCAGTATAATAACTGGCCTCCTCTCACT 63 993 993 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCAAGGCTTCAGGAGACACCTTCAGCATGT ATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGG ATGGGAGGGGTCCTCCCAATGTTAGGGACCTCAAACTACGCACAACA GTTCCGGGGCAGAGTCACGATAACGGCGGACGGATCCACGAGCACA GCCTACATGGAGATGAGCAACCTGAGATTTGAGGACACGGCCGTTTA TTACTGTGCGAGGGTGGCCGGTCTGGGGAACAGCTATGGTCGCTACT TTGACGTCTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA 63 994 994 QVQLVQSGAEVKKPGSSVKVSCKASGDTFSMYAISWVRQAPGQGLEW MGGVLPMLGTSNYAQQFRGRVTITADGSTSTAYMEMSNLRFEDTAVYY CARVAGLGNSYGRYFDVWGQGTLVTVSS 63 995 995 DTFSMYAIS 63 996 996 GACACCTTCAGCATGTATGCTATCAGC 63 997 997 GVLPMLGTSNYAQQFRG 63 998 998 GGGGTCCTCCCAATGTTAGGGACCTCAAACTACGCACAACAGTTCCG GGGC 63 999 999 ARVAGLGNSYGRYFDV 63 1000 1000 GCGAGGGTGGCCGGTCTGGGGAACAGCTATGGTCGCTACTTTGACGTC 63 1001 1001 GACATCCGGATGACCCAGTCTCCATCTTCTGTGTCTGCATCTATTGGG GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGATATCAGCACCTC GTTAGCCTGGTATCAGCAAAGACCAGGGAAAGCCCCTAATCTCCTGA TCTATGCTGCGTCCACTTTACACAGTGGGGTCCCATCGAGGTTCAGGG GCAGTGAATCTGGCCCAGACTTCACTCTCACTATCAGCAGCCTGCAGC CTGAAGATGTCGGAACTTACTATTGTCAACAGGCAAAGAGTTTCCCG TACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 63 1002 1002 DIRMTQSPSSVSASIGDRVTITCRASQDISTSLAWYQQRPGKAPNLLIYAA STLHSGVPSRFRGSESGPDFTLTISSLQPEDVGTYYCQQAKSFPYTFGQGT KLEIK 63 1003 1003 RASQDISTSLA 63 1004 1004 CGGGCGAGTCAGGATATCAGCACCTCGTTAGCC 63 1005 1005 AASTLHS 63 1006 1006 GCTGCGTCCACTTTACACAGT 63 1007 1007 QQAKSFPYT 63 1008 1008 CAACAGGCAAAGAGTTTCCCGTACACT 64 1009 1009 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCAGCCTCACAAACTA CAGAATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG GTCTCATCCCTTAAGGATTCTAGTTCTTACATCTACTACGCAGACTCA GTGAAGGGCCGATTCACCGTCTCCAGAGACGACGCGAAGAATTCATT CTTTTTGCAAATGACCAATGTAAGAGCCGAGGACACGGCTGTTTATTA CTGTGCGAGAGAGGGATCGGACACGGAGTATTGGAGGCTGACGCCCC CCATGGACGTCTGGGGCAACGGGACCACGGTCACCGTCTCCTCA 64 1010 1010 QVQLVQSGGGLVKPGGSLRLSCAASGFSLTNYRMNWVRQAPGKGLEW VSSLKDSSSYIYYADSVKGRFTVSRDDAKNSFFLQMTNVRAEDTAVYYC AREGSDTEYWRLTPPMDVWGNGTTVTVSS 64 1011 1011 FSLTNYRMN 64 1012 1012 TTCAGCCTCACAAACTACAGAATGAAC 64 1013 1013 SLKDSSSYIYYADSVKG 64 1014 1014 TCCCTTAAGGATTCTAGTTCTTACATCTACTACGCAGACTCAGTGAAG GGC 64 1015 1015 AREGSDTEYWRLTPPMDV 64 1016 1016 GCGAGAGAGGGATCGGACACGGAGTATTGGAGGCTGACGCCCCCCAT GGACGTC 64 1017 1017 CAGTCTGTGTTGACGCAGCCGCCCTCGGTGTCAGTGGCCCCACGACA GACGGCCAGGATTACCTGTGGGGAGCACAACATTGGAACTAAAAGTG TGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTCCTGGTCATC TATGATGACAGCGACCGGCCCTCAGGGATCCCTGCGCGATTCTCTGG CTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCTGGGTCGAAG CCGGGGATGAGGCCGTCTATTACTGTCAGGTGTGGGACTCAGGTGAT CATCCTTGGCTGTTCGGCGGAGGCACCCAGCTGACCGTCCTC 64 1018 1018 QSVLTQPPSVSVAPRQTARITCGEHNIGTKSVHWYQQKPGQAPVLVIYD DSDRPSGIPARFSGSNSGNTATLTISWVEAGDEAVYYCQVWDSGDHPWL FGGGTQLTVL 64 1019 1019 GEHNIGTKSVH 64 1020 1020 GGGGAGCACAACATTGGAACTAAAAGTGTGCAC 64 1021 1021 DDSDRPS 64 1022 1022 GATGACAGCGACCGGCCCTCA 64 1023 1023 QVWDSGDHPWL 64 1024 1024 CAGGTGTGGGACTCAGGTGATCATCCTTGGCTG 65 1025 1025 GAGGTGCAGCTGGTGGAGTCAGGGGGAGGCTTGGTACAGCCGGGGG GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCCCCTTCAGTCGTT ATAACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG GTTTCATACATTAGTAGTGGTAGTCGAAGCATTTACTACGCAGACTCT GTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACT GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATT ACTGTGCGAGAGACTTAAGCGGATCTCCAGCATATAGCGGCAGCTGG GTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 65 1026 1026 EVQLVESGGGLVQPGGSLRLSCAASGFPFSRYNMNWVRQAPGKGLEWV SYISSGSRSIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR DLSGSPAYSGSWVWGQGTLVTVSS 65 1027 1027 FPFSRYNMN 65 1028 1028 TTCCCCTTCAGTCGTTATAACATGAAC 65 1029 1029 YISSGSRSIYYADSVKG 65 1030 1030 TACATTAGTAGTGGTAGTCGAAGCATTTACTACGCAGACTCTGTGAA GGGC 65 1031 1031 ARDLSGSPAYSGSWV 65 1032 1032 GCGAGAGACTTAAGCGGATCTCCAGCATATAGCGGCAGCTGGGTC 65 1033 1033 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGG GGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCA ACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTC ATCTATGATGCATCCACCAGGGCCACTGGTATCCCAGACAGGTTCAG TGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGC AGTCTGAAGACTTTGCACTTTATTACTGTCAGCAGTATGATAGGTGGC CTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 65 1034 1034 ETTLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYD ASTRATGIPDRFSGSGSGTEFTLTISSLQSEDFALYYCQQYDRWPPWTFG QGTKVEIK 65 1035 1035 RASQSVSSNLA 65 1036 1036 AGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCC 65 1037 1037 DASTRAT 65 1038 1038 GATGCATCCACCAGGGCCACT 65 1039 1039 QQYDRWPPWT 65 1040 1040 CAGCAGTATGATAGGTGGCCTCCGTGGACG 66 1041 1041 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGAAACTCCTTCAACGACTT TTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGATGGATCGACCCTAACAACGGAGGCGCAAACTATGCACAGAA GTTTCATGGCAGGGTCACTATGACCAGGGACTCGTCCATCAACACAG CCTACATGGAGTTGAGCAGGCTGAGATCCGACGACACGGCCGTCTAT TACTGTGCGAGCGAGCCCCCCGGCGTTGGTTTTGGATTGATTCCCCAC TACTACTTTGACAACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 66 1042 1042 QVQLVQSGAEVKKPGASVKVSCKASGNSFNDFYMHWVRQAPGQGLEW MGWIDPNNGGANYAQKFHGRVTMTRDSSINTAYMELSRLRSDDTAVYY CASEPPGVGFGLIPHYYFDNWGQGTLVTVSS 66 1043 1043 NSFNDFYMH 66 1044 1044 AACTCCTTCAACGACTTTTATATGCAC 66 1045 1045 WIDPNNGGANYAQKFHG 66 1046 1046 TGGATCGACCCTAACAACGGAGGCGCAAACTATGCACAGAAGTTTCA TGGC 66 1047 1047 ASEPPGVGFGLIPHYYFDN 66 1048 1048 GCGAGCGAGCCCCCCGGCGTTGGTTTTGGATTGATTCCCCACTACTAC TTTGACAAC 66 1049 1049 GAAATTGTGATGACACAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAATGTTTTAGACAC CTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGAC AGCCTCCTAGACTGCTCATTTACTGGGCATCTGCCCGCGGATCCGGGG TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACACATTTCACTCTCA CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAG CAATATTTTAGTATTCCTCCGACGTTCGGCCAAGGGACCAAGGTGGA GATCAAA 66 1050 1050 EIVMTQSPDSLAVSLGERATINCKSSQNVLDTSNNKNYLAWYQQKPGQP PRLLIYWASARGSGVPDRFSGSGSGTHFTLTISSLQAEDVAVYYCQQYFSI PPTFGQGTKVEIK 66 1051 1051 KSSQNVLDTSNNKNYLA 66 1052 1052 AAGTCCAGCCAGAATGTTTTAGACACCTCCAACAATAAGAACTACTT AGCT 66 1053 1053 WASARGS 66 1054 1054 TGGGCATCTGCCCGCGGATCC 66 1055 1055 QQYFSIPPT 66 1056 1056 CAGCAATATTTTAGTATTCCTCCGACG 67 1057 1057 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCAAGGTTGCCGGAGGCTCCTTCTCCAATTA TGCAATCGCCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGAGGTATCATCCCTGCCTTTAACAGAGCAATGTATGCACGGAAG TTCCAAGACAGAGTCACAATTACCGCGTACGCATCAACGACCACTGC CTACCTGGACATTACCGGCCTCAGATCTGAGGACACGGCCCTTTATTA TTGTGCGAGGCCTGCTGGAGACTTTGGGGATTTAAAGTGGGTACGAT CGCCTTTTGACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCA 67 1058 1058 QVQLVQSGAEVKKPGSSVKVSCKVAGGSFSNYAIAWLRQAPGQGLEW MGGIIPAFNRAMYARKFQDRVTITAYASTTTAYLDITGLRSEDTALYYCA RPAGDFGDLKWVRSPFDYWGQGTLITVSS 67 1059 1059 GSFSNYAIA 67 1060 1060 GGCTCCTTCTCCAATTATGCAATCGCC 67 1061 1061 GIIPAFNRAMYARKFQD 67 1062 1062 GGTATCATCCCTGCCTTTAACAGAGCAATGTATGCACGGAAGTTCCA AGAC 67 1063 1063 ARPAGDFGDLKWVRSPFDY 67 1064 1064 GCGAGGCCTGCTGGAGACTTTGGGGATTTAAAGTGGGTACGATCGCC TTTTGACTAC 67 1065 1065 GATATTGTGATGACGCAGACTCCAGGCACCCTGTCTGTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGGACGTTGGCATCAA CTTAGCCTGGTATCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCCTCAT ATATGGTGCATCCACCAGGGCCACTGATGTCCCAGCCAAGTTCAGTG GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAG TCTGAAGATTTTGGAGTTTATTATTGTCAGGAGTATAATGACTGGCCT CCCCAGCTCTCTTTCGGCCCTGGGACCAAAGTGGATATCAAA 67 1066 1066 DIVMTQTPGTLSVSPGERATLSCRASQDVGINLAWYQQKPGQAPRLLIY GASTRATDVPAKFSGSGSGTDFTLTISSLQSEDFGVYYCQEYNDWPPQLS FGPGTKVDIK 67 1067 1067 RASQDVGINLA 67 1068 1068 AGGGCCAGTCAGGACGTTGGCATCAACTTAGCC 67 1069 1069 GASTRAT 67 1070 1070 GGTGCATCCACCAGGGCCACT 67 1071 1071 QEYNDWPPQLS 67 1072 1072 CAGGAGTATAATGACTGGCCTCCCCAGCTCTCT 68 1073 1073 CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACA GACCCTCACACTGACCTGCACCCTCTCTGGGTTCTCACTCAGCACTCC TAGAATGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGG AGTGGCTTGCACTCATTGATTGGGATGATGATAGGCGCTACAGTCCAT CTCTGAAGACCAGGCTCACCATCACCAAGGACACTTCCAAAAATCAG GTGGTCCTTAGAATGACCGACATGGACCCTGTGGACACAGGCACATA TTACTGTGTACACAGCGATGTCTATACTACTGGTGGTTATTACTTGTA CTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 68 1074 1074 QITLKESGPTLVKPTQTLTLTCTLSGFSLSTPRMGVGWIRQPPGKALEWL ALIDWDDDRRYSPSLKTRLTITKDTSKNQVVLRMTDMDPVDTGTYYCV HSDVYTTGGYYLYYFDYWGQGTLVTVSS 68 1075 1075 FSLSTPRMGVG 68 1076 1076 TTCTCACTCAGCACTCCTAGAATGGGTGTGGGC 68 1077 1077 LIDWDDDRRYSPSLKT 68 1078 1078 CTCATTGATTGGGATGATGATAGGCGCTACAGTCCATCTCTGAAGACC 68 1079 1079 VHSDVYTTGGYYLYYFDY 68 1080 1080 GTACACAGCGATGTCTATACTACTGGTGGTTATTACTTGTACTACTTT GACTAC 68 1081 1081 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTCCCAGCTA TTTAAATTGGTATCAGCACAAACCAGGGAAAGCCCCTCAGCTCCTGA TCTATGCTGCATCCAATTTGCGAAGTGGGGTCCCACCGAGGTTCCGTG GCAGTGGATCTGGGACAGATTTCACTCTCACCGTCAGCAGTCTGCAA CCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTAGCCCA TACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 68 1082 1082 DIQVTQSPSSLSASVGDRVTITCRASQTIPSYLNWYQHKPGKAPQLLIYAA SNLRSGVPPRFRGSGSGTDFTLTVSSLQPEDFATYFCQQSYSSPYTFGQGT KLEIK 68 1083 1083 RASQTIPSYLN 68 1084 1084 CGGGCAAGTCAGACCATTCCCAGCTATTTAAAT 68 1085 1085 AASNLRS 68 1086 1086 GCTGCATCCAATTTGCGAAGT 68 1087 1087 QQSYSSPYT 68 1088 1088 CAACAGAGTTACAGTAGCCCATACACT 69 1089 1089 CAGGTCCAGCTGGTACAGTCTGGAACTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAGGTCTCCTGCAAGGGCTCTGGTTACATGTTTGCAAATTT TGGTGTCAGCTGGGTGCGACAGGCCCCTGGACGAGGGCTTGAGTGGA TCGGATGGATCAGCGCTTACAATGGAAACACATACTATGGACGTGAG CAGGGCAGATTCACCATGACCACAGACACGAACACAGCCTACCTGGA GCTGACGAGTCTCAGATATGACGACACGGCCCTTTATTTCTGTGCGAG AGATTCGGGAGCGACGGCGGCTGGAATACTCTGGGACTATTGGGGCC AGGGAACCCTGGTCACCGTCTCCTCA 69 1090 1090 QVQLVQSGTEVKKPGASVKVSCKGSGYMFANFGVSWVRQAPGRGLEW IGWISAYNGNTYYGREQGRFTMTTDTNTAYLELTSLRYDDTALYFCARD SGATAAGILWDYWGQGTLVTVSS 69 1091 1091 YMFANFGVS 69 1092 1092 TACATGTTTGCAAATTTTGGTGTCAGC 69 1093 1093 WISAYNGNTYYGREQG 69 1094 1094 TGGATCAGCGCTTACAATGGAAACACATACTATGGACGTGAGCAGGGC 69 1095 1095 ARDSGATAAGILWDY 69 1096 1096 GCGAGAGATTCGGGAGCGACGGCGGCTGGAATACTCTGGGACTAT 69 1097 1097 GAAATTGTAATGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGCATACACT GATGGAAGCACTTACTTGAATTGGTTTCACCAGAGGCCAGGCCAGTC TCCACGGCGCCTAATTTATAAGGTTTTTAACCGGGACTCTGGGGTCCC CGACAGATTCAGCGGCAGTGGGGCAGGCACTGATTTCACACTGACTA TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA GCTACACACTGGCCTCGGACGTTCGGCCAGGGGACCAAAGTGGATAT CAAA 69 1098 1098 EIVMTQSPLSLPVTLGQPASISCRSSQSLAYTDGSTYLNWFHQRPGQSPRR LIYKVFNRDSGVPDRFSGSGAGTDFTLTISRVEAEDVGVYYCMQATHWP RTFGQGTKVDIK 69 1099 1099 RSSQSLAYTDGSTYLN 69 1100 1100 AGGTCTAGTCAAAGCCTCGCATACACTGATGGAAGCACTTACTTGAAT 69 1101 1101 KVFNRDS 69 1102 1102 AAGGTTTTTAACCGGGACTCT 69 1103 1103 MQATHWPRT 69 1104 1104 ATGCAAGCTACACACTGGCCTCGGACG 70 1105 1105 CAGGTCCAGCTGGTACAGTCTGGAAGTGAGGTGAAGAAGCCTGGGGC CTCGGTGACGCTCTCCTGCAAGGCCTCAGGTTACAGGTTTTCCAACTA TGGTGTCAGCTGGGTGCGACAGGCCCCCGGACAAGGCCTAGAGTGGA TGGGATGGATCAGCGGTTACAATGGAAACATAAAGTATGGAAACAGT CTCCAGGGCAGAGTCACCCTGACCACAGACACGACCACGGCCTACAT GGAGGTGACGAGCCTAACATCTGACGACACGGCCGTGTATTACTGTG CGAGAGATGTCCCAGCTGACGGGGTCCACTTCATGGACGTCTGGGGC AAAGGGACCACGGTCACCGTCTCCTCA 70 1106 1106 QVQLVQSGSEVKKPGASVTLSCKASGYRFSNYGVSWVRQAPGQGLEW MGWISGYNGNIKYGNSLQGRVTLTTDTTTAYMEVTSLTSDDTAVYYCA RDVPADGVHFMDVWGKGTTVTVSS 70 1107 1107 YRFSNYGVS 70 1108 1108 TACAGGTTTTCCAACTATGGTGTCAGC 70 1109 1109 WISGYNGNIKYGNSLQG 70 1110 1110 TGGATCAGCGGTTACAATGGAAACATAAAGTATGGAAACAGTCTCCA GGGC 70 1111 1111 ARDVPADGVHFMDV 70 1112 1112 GCGAGAGATGTCCCAGCTGACGGGGTCCACTTCATGGACGTC 70 1113 1113 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTCCACAGT GATACTAACACCTACTTGACCTGGTTTCAGCAGAGGCCAGGCCAATC TCCACGGCGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACAACTTTCACGCTGAAAA TCGCCAGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGGAG GGGTCACACTGGGCTCCGACTTTCGGCCAGGGGACCAAAGTGGATAT CAAA 70 1114 1114 EIVLTQSPLSLPVTLGQPASISCRSSQSLVHSDTNTYLTWFQQRPGQSPRR LIYKVSHRDSGVPDRFSGSGSGTTFTLKIARVEAEDVGIYYCMEGSHWAP TFGQGTKVDIK 70 1115 1115 RSSQSLVHSDTNTYLT 70 1116 1116 AGGTCTAGTCAAAGCCTCGTCCACAGTGATACTAACACCTACTTGACC 70 1117 1117 KVSHRDS 70 1118 1118 AAGGTTTCTCACCGGGACTCT 70 1119 1119 MEGSHWAPT 70 1120 1120 ATGGAGGGGTCACACTGGGCTCCGACT 71 1121 1121 CAGGTGCAGCTACAGCAGTGGGGGGCCGAGGTGAAGAAGCCTGGGT CATCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGTCGCCTTGAGCAGC GTTGCAATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTG GATGGGAGGGATCCTCCCTGGGTTTGACAAGGTCAGATTTGCCCAGG AGTTTGAGAATAGAGCCACTCTAACCGCGGACACAGCTAGGGATATA GCCTACATGGAGTTGAGCGGACTGAGATCTGACGACACGGCCGTCTA CTACTGTGCGATAATCGACCCCCAAGATTGCACTAGTGCCAGCTGCTT TTGGGTCAACTGGCTCGACCCCTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA 71 1122 1122 QVQLQQWGAEVKKPGSSVKVSCKASGVALSSVAISWVRQAPGQGLEW MGGILPGFDKVRFAQEFENRATLTADTARDIAYMELSGLRSDDTAVYYC AIIDPQDCTSASCFWVNWLDPWGQGTLVTVSS 71 1123 1123 VALSSVAIS 71 1124 1124 GTCGCCTTGAGCAGCGTTGCAATCAGC 71 1125 1125 GILPGFDKVRFAQEFEN 71 1126 1126 GGGATCCTCCCTGGGTTTGACAAGGTCAGATTTGCCCAGGAGTTTGA GAAT 71 1127 1127 AIIDPQDCTSASCFWVNWLDP 71 1128 1128 GCGATAATCGACCCCCAAGATTGCACTAGTGCCAGCTGCTTTTGGGTC AACTGGCTCGACCCC 71 1129 1129 GAAACGACACTCACGCAGTCTCCAGGCACCCTGACCGTGTCTCCAGG GGAGAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTATTAGAA ACAACCTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTC CTCATCTATGCTGCATCCAATAGGGCCACTGACATCCCAGACAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACT GGAAGCACAAGATTTTGCAGTGTATTTCTGTCAGCAGTATGGTACCTC TCCGATCACCTTCGGCCAAGGGACCAAGGTGGAAATCAAA 71 1130 1130 ETTLTQSPGTLTVSPGERATLSCRASQSIIRNNLAWYQQKPGQAPRLLIYA ASNRATDIPDRFSGSGSGTDFTLTISRLEAQDFAVYFCQQYGTSPITFGQG TKVEIK 71 1131 1131 RASQSIIRNNLA 71 1132 1132 AGGGCCAGTCAGAGTATTATTAGAAACAACCTAGCC 71 1133 1133 AASNRAT 71 1134 1134 GCTGCATCCAATAGGGCCACT 71 1135 1135 QQYGTSPIT 71 1136 1136 CAGCAGTATGGTACCTCTCCGATCACC 72 1137 1137 GAGGTGCAGCTGTTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCAAGGTTGCCGGAGGAACCTTCAGCGACT ACGCCATCAGCTGGGTGCGACAGGCCCCTGGTCAAGGGCTGGAGTAC TTGGGAGGGATCATTCCTGCCTTTAAAAGAGCAATGTATCCACGGAA GTTTCAAGACAGAGTCACCATTACCGCGGACGAGTCCACGAGCACTG CCTACATGGAGCTGAGAGGCCTGAGATCTGAAGACACGGCCCTGTAT TATTGTGCGAGACCTGCTGGAGACTTTGGCGATTTAAAGTGGCTACG ATCGCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 72 1138 1138 EVQLLESGAEVKKPGSSVKVSCKVAGGTFSDYAISWVRQAPGQGLEYLG GIIPAFKRAMYPRKFQDRVTITADESTSTAYMELRGLRSEDTALYYCARP AGDFGDLKWLRSPFDYWGQGTLVTVSS 72 1139 1139 GTFSDYAIS 72 1140 1140 GGAACCTTCAGCGACTACGCCATCAGC 72 1141 1141 GIIPAFKRAMYPRKFQD 72 1142 1142 GGGATCATTCCTGCCTTTAAAAGAGCAATGTATCCACGGAAGTTTCA AGAC 72 1143 1143 ARPAGDFGDLKWLRSPFDY 72 1144 1144 GCGAGACCTGCTGGAGACTTTGGCGATTTAAAGTGGCTACGATCGCC TTTTGACTAC 72 1145 1145 GATATTGTGCTGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG GAAAGAGCCACGCTCTCCTGCAGGGCCAGTGAGGGTGTAGGCATCAA CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATGGTGCATCGACCAGGGCCACTGATATCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCA ATCTGAAGATTTTGCAGTTTATTATTGTCAGCAGTATAATGATTGGCC TCCCCAGCTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 72 1146 1146 DIVLTQSPATLSVSPGERATLSCRASEGVGINLAWYQQKPGQAPRLLIYG ASTRATDIPARFSGSGSGTDFTLTISSLQSEDFAVYYCQQYNDWPPQLTF GPGTKVDIK 72 1147 1147 RASEGVGINLA 72 1148 1148 AGGGCCAGTGAGGGTGTAGGCATCAACTTAGCC 72 1149 1149 GASTRAT 72 1150 1150 GGTGCATCGACCAGGGCCACT 72 1151 1151 QQYNDWPPQLT 72 1152 1152 CAGCAGTATAATGATTGGCCTCCCCAGCTCACT 73 1153 1153 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGTAAGGTTGTCGGAGGCAGTTTCAGCAACT ATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAGGGGCCTGAGTGG ATGGGCGGGATCATCCCTGCCTTTAAGACAGCAAAATATGCAAAGAA GTTCGAGGACAGAGTCACAATTACCGCGGACGAATCCACGAGCACTG CCTACATGGAGGTGAGCGGCCTGAGATCTGACGACACGGCCCTGTAT TATTGTGCGAGGCCTGAACGAGACTTTGGGCATTTAAAGTGGCTACG CTCGCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 73 1154 1154 EVQLVESGAEVKKPGSSVKVSCKVVGGSFSNYGISWVRQAPGQGPEWM GGIIPAFKTAKYAKKFEDRVTITADESTSTAYMEVSGLRSDDTALYYCAR PERDFGHLKWLRSPFDYWGQGTLVTVSS 73 1155 1155 GSFSNYGIS 73 1156 1156 GGCAGTTTCAGCAACTATGGTATCAGC 73 1157 1157 GIIPAFKTAKYAKKFED 73 1158 1158 GGGATCATCCCTGCCTTTAAGACAGCAAAATATGCAAAGAAGTTCGA GGAC 73 1159 1159 ARPERDFGHLKWLRSPFDY 73 1160 1160 GCGAGGCCTGAACGAGACTTTGGGCATTTAAAGTGGCTACGCTCGCC TTTTGACTAC 73 1161 1161 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGG GGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGGGTGTTAGCATCA ACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTC ATCTATGGTGCATCCACCAGGGCCACTGATATCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCA GTCTGAAGATTTTGCAGTTTATTATTGTCAGCAGTATAATGACTGGCC TCCCCAGCTCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 73 1162 1162 ETTLTQSPATLSVSPGERVTLSCRASQGVSINLAWYQQKPGQAPRLLIYG ASTRATDIPARFSGSGSGTDFTLTISSLQSEDFAVYYCQQYNDWPPQLTF GPGTKVEIK 73 1163 1163 RASQGVSINLA 73 1164 1164 AGGGCCAGTCAGGGTGTTAGCATCAACTTAGCC 73 1165 1165 GASTRAT 73 1166 1166 GGTGCATCCACCAGGGCCACT 73 1167 1167 QQYNDWPPQLT 73 1168 1168 CAGCAGTATAATGACTGGCCTCCCCAGCTCACT 74 1169 1169 CAGGTCCAGCTGGTGCAGTCTGGGTCTGAGGTGAAGAGGCCTGGGTC ATCGGTGAAGGTCTCCTGCAAGGCCTCAGGAGTCGCTTTGACCACCG TTGCTGTCAACTGGGTGCGCCAGGTCCCTGGGCAAGGGCCTGAGTGG ATTGGAGGGATCCTCATTGGGTTTGGTAAGGTCAGACAGGCCCAGAA ATTTGAGAACCGAGTCACTTTTACCGCGGACGCATCTAGGAACACAG CCTACATGGAGTTGAGCGGACTGAGATCTGAGGACACGGCCGTCTAT TACTGTGCGATAATCGACCCCCAAGATTGTACTCGTGCCAGTTGCTTT TGGGTCAACTGGCTCGCCCCCTGGGGCCACGGAACCCTGGTCACCGT CTCCTCA 74 1170 1170 QVQLVQSGSEVKRPGSSVKVSCKASGVALTTVAVNWVRQVPGQGPEWI GGILIGFGKVRQAQKFENRVTFTADASRNTAYMELSGLRSEDTAVYYCA IIDPQDCTRASCFWVNWLAPWGHGTLVTVSS 74 1171 1171 VALTTVAVN 74 1172 1172 GTCGCTTTGACCACCGTTGCTGTCAAC 74 1173 1173 GILIGFGKVRQAQKFEN 74 1174 1174 GGGATCCTCATTGGGTTTGGTAAGGTCAGACAGGCCCAGAAATTTGA GAAC 74 1175 1175 AIIDPQDCTRASCFWVNWLAP 74 1176 1176 GCGATAATCGACCCCCAAGATTGTACTCGTGCCAGTTGCTTTTGGGTC AACTGGCTCGCCCCC 74 1177 1177 GACATCCGGGTGACCCAGTCTCCAGGCACCCTGACCTTGTCCCCAGG GGAGAGAGCCTCCCTCTCCTGCAGGGCCAGTGAGAGTATTCTTAACG GGAACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTC CTCATCTATGCTGCTTCCAGTAGGGCCACTGACATCCCAGACAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACT GGAGCCTCAAGATTTTGCAGTCTATTATTGTCAGCAGTATGGTTCGGC TCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 74 1178 1178 DIRVTQSPGTLTLSPGERASLSCRASESILNGNLAWYQQKPGQAPRLLIYA ASSRATDIPDRFSGSGSGTDFTLTISRLEPQDFAVYYCQQYGSAPITFGQG TRLEIK 74 1179 1179 RASESILNGNLA 74 1180 1180 AGGGCCAGTGAGAGTATTCTTAACGGGAACTTAGCC 74 1181 1181 AASSRAT 74 1182 1182 GCTGCTTCCAGTAGGGCCACT 74 1183 1183 QQYGSAPIT 74 1184 1184 CAGCAGTATGGTTCGGCTCCGATCACC 75 1185 1185 CAGGTCCAGCTTGTACAGTCTGGAAGTGAGGTGAAGAAGCCTGGGGC CTCGGTGACGGTCTCCTGCAAGGCCTCAGGTTACAGGTTTTCCAACTA TGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGCCTAGAGTGGA TGGGATGGATCAGCGCTTACAATGGAAACACAAAGTATGGAAATAGT CTCCAGGGCAGAGTCACCCTGACCACAGACACGACCACGGCCTACAT GGAGGTGAGGAGCCTGACATCTGACGACACGGCCGTGTATTACTGTG CGAGAGATGTCCCAGGTGACGGGGTCCACTTCATGGACGTCTGGGGC AAAGGGACCACGGTCACCGTCTCCTCA 75 1186 1186 QVQLVQSGSEVKKPGASVTVSCKASGYRFSNYGVSWVRQAPGQGLEW MGWISAYNGNTKYGNSLQGRVTLTTDTTTAYMEVRSLTSDDTAVYYCA RDVPGDGVHFMDVWGKGTTVTVSS 75 1187 1187 YRFSNYGVS 75 1188 1188 TACAGGTTTTCCAACTATGGTGTCAGC 75 1189 1189 WISAYNGNTKYGNSLQG 75 1190 1190 TGGATCAGCGCTTACAATGGAAACACAAAGTATGGAAATAGTCTCCA GGGC 75 1191 1191 ARDVPGDGVHFMDV 75 1192 1192 GCGAGAGATGTCCCAGGTGACGGGGTCCACTTCATGGACGTC 75 1193 1193 GAAATTGTGATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGTCGGCCTCCATCTCCTGCAGGTCGAGTCAAAGCCTCGTACACAGT GATACTAACACCTACTTGACCTGGTTTCAGCAGAGGCCAGGCCAATC TCCACGGCGCCTCATTTATAAGGTTTCTCACCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTACTTTTACACTGAAAA TCAGCAGGGTGGAGGCTGAGGATGTTGGAATTTATTACTGCATGGAG GGTTCACACTGGGCTCCGACTTTCGGCCAGGGGACCAAGGTGGAAAT CAAA 75 1194 1194 EIVMTQSPLSLPVTLGQSASISCRSSQSLVHSDTNTYLTWFQQRPGQSPRR LIYKVSHRDSGVPDRFSGSGSGTTFTLKISRVEAEDVGIYYCMEGSHWAP TFGQGTKVEIK 75 1195 1195 RSSQSLVHSDTNTYLT 75 1196 1196 AGGTCGAGTCAAAGCCTCGTACACAGTGATACTAACACCTACTTGACC 75 1197 1197 KVSHRDS 75 1198 1198 AAGGTTTCTCACCGGGACTCT 75 1199 1199 MEGSHWAPT 75 1200 1200 ATGGAGGGTTCACACTGGGCTCCGACT 76 1201 1201 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCGTTGTCCAGCCTGGGAG CTCCCTGAGACTCTCCTGTTCAGCGTCTGGATTTACCTTCATGACCTAT GGCATGCACTGGGCCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGT CGCAGATATTTCCTTTGATGCAAATAAGAAATACTATAGAGATTCCGT GAAGGGCCGATTCACCATCTCCAGGGACAATTCCAAGAACACGGTGT ATCTGCAAATGAACAGCCTGAGACCCGAGGACACGGCTGTCTACTTC TGTGCGAGAAATACGATTTTTGGAGTAGTTGACTACTGGGGCCAGGG AACCCTGGTCACCGTCTCCTCA 76 1202 1202 QVQLVQSGGGVVQPGSSLRLSCSASGFTFMTYGMHWARQAPGKGLEW VADISFDANKKYYRDSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYFC ARNTIFGVVDYWGQGTLVTVSS 76 1203 1203 FTFMTYGMH 76 1204 1204 TTTACCTTCATGACCTATGGCATGCAC 76 1205 1205 DISFDANKKYYRDSVKG 76 1206 1206 GATATTTCCTTTGATGCAAATAAGAAATACTATAGAGATTCCGTGAAG GGC 76 1207 1207 ARNTIFGVVDY 76 1208 1208 GCGAGAAATACGATTTTTGGAGTAGTTGACTAC 76 1209 1209 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCGCCAA CTTAGCCTGGTACCAGCATAAACCTGGCCAGGCTCCCAGGCTCCTCAT CTATGGTGCGTCCACCAGGGCCAGTGATATCCCAGCCAGGTTCAGTG GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG TCTGAAGATTCTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCT CCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 76 1210 1210 EIVLTQSPATLSVSPGERATLSCRASQSVSANLAWYQHKPGQAPRLLIYG ASTRASDIPARFSGSGSGTEFTLTISSLQSEDSAVYYCQQYNNWPPWTFG QGTKVEIK 76 1211 1211 RASQSVSANLA 76 1212 1212 AGGGCCAGTCAGAGTGTTAGCGCCAACTTAGCC 76 1213 1213 GASTRAS 76 1214 1214 GGTGCGTCCACCAGGGCCAGT 76 1215 1215 QQYNNWPPWT 76 1216 1216 CAGCAGTATAATAACTGGCCTCCGTGGACG 77 1217 1217 CAGGTCCAGCTGGTGCAGTCTGGAGTTGAGGTGAAGAAGCCTGGGGC CTCAGTGAAGGTCTCCTGCAAGACTTCTGGTTACACCTTTAGTAATTA TGGTGTCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTACA TGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCCCAGAAT GTCCAGGGTCGACTCACCATGACCACAGACACATCCACGAGCACAGG CTACATGGAGTTGAGGAGGCTGACATCTGACGACACGGCCGTGTATT TCTGTGCGAGAGATAAAGGTGTAACAGTGGCCGGTTCATTGCTTGAC TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 77 1218 1218 QVQLVQSGVEVKKPGASVKVSCKTSGYTFSNYGVTWVRQAPGQGLEY MGWISAYNGNTNYAQNVQGRLTMTTDTSTSTGYMELRRLTSDDTAVYF CARDKGVTVAGSLLDYWGQGTLVTVSS 77 1219 1219 YTFSNYGVT 77 1220 1220 TACACCTTTAGTAATTATGGTGTCACC 77 1221 1221 WISAYNGNTNYAQNVQG 77 1222 1222 TGGATCAGCGCTTACAATGGTAACACAAACTATGCCCAGAATGTCCA GGGT 77 1223 1223 ARDKGVTVAGSLLDY 77 1224 1224 GCGAGAGATAAAGGTGTAACAGTGGCCGGTTCATTGCTTGACTAC 77 1225 1225 GAAATTGTGATGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGTCTCGAACATAGT GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC TCCAAGGCGCCTCATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA TCAACAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGGAA AGTACACACTGGCCTCCGTACACTTTTGGCCAGGGGACCAAGGTGGA GATCAAA 77 1226 1226 EIVMTQSPLSLPVTLGQPASISCRSSQSLEHSDGNTYLNWFQQRPGQSPRR LIYKVSNRDSGVPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMESTHWP PYTFGQGTKVEIK 77 1227 1227 RSSQSLEHSDGNTYLN 77 1228 1228 AGGTCTAGTCAAAGTCTCGAACATAGTGATGGAAACACCTACTTGAAT 77 1229 1229 KVSNRDS 77 1230 1230 AAGGTTTCTAACCGGGACTCT 77 1231 1231 MESTHWPPYT 77 1232 1232 ATGGAAAGTACACACTGGCCTCCGTACACT 78 1233 1233 CAGGTCCAGCTGGTGCAGTCTGGACCTGAGGTGAAGAAGCCTGGGGC CTCAGTGCGGGTCTCCTGCAAGACTTCTGGTTTCACCTTGTCCCATTA TGGTGTCAGTTGGCTGCGGCAGGCCCCTGGACACGGACTTGAGTGGC TGGGCTGGATCAGCGCTTACAACTATAACACACAATTTGGACACAGA ATGGAGGGCAGGCTCACCATGACCACAGACACTTCCACAGCCTATAT GGACCTGACGAGCCTGACTTCTGACGACACGGCCATATATTACTGTG CGAGAGATTCCCCTTCAGACACAGCGGCAGCACTCCTTGACTTCTGG GGCCAGGGAACCCTGGTCACCGTCTCCTCA 78 1234 1234 QVQLVQSGPEVKKPGASVRVSCKTSGFTLSHYGVSWLRQAPGHGLEWL GWISAYNYNTQFGHRMEGRLTMTTDTSTAYMDLTSLTSDDTAIYYCAR DSPSDTAAALLDFWGQGTLVTVSS 78 1235 1235 FTLSHYGVS 78 1236 1236 TTCACCTTGTCCCATTATGGTGTCAGT 78 1237 1237 WISAYNYNTQFGHRMEG 78 1238 1238 TGGATCAGCGCTTACAACTATAACACACAATTTGGACACAGAATGGA GGGC 78 1239 1239 ARDSPSDTAAALLDF 78 1240 1240 GCGAGAGATTCCCCTTCAGACACAGCGGCAGCACTCCTTGACTTC 78 1241 1241 GATATTGTGCTGACTCAGTCTCCCCTCTCCCTGCCCGTCACTCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGT GATGGCAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAAGC TCCAAGGCGCCTAATTTATAAGATTTCTAACCGAGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTAAAGA TCAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCAA GCTACACACTGGCCTCGTCTCAGTTTCGGCGGAGGGACCAAGGTGGA GATCAAA 78 1242 1242 DIVLTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLSWFQQRPGQAPRR LIYKISNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYCMQATHWPR LSFGGGTKVEIK 78 1243 1243 RSSQSLVYSDGNTYLS 78 1244 1244 AGGTCTAGTCAAAGCCTCGTATACAGTGATGGCAACACCTACTTGAGT 78 1245 1245 KISNRDS 78 1246 1246 AAGATTTCTAACCGAGACTCT 78 1247 1247 MQATHWPRLS 78 1248 1248 ATGCAAGCTACACACTGGCCTCGTCTCAGT 79 1249 1249 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAAATGAAGCAGCCTGGGGC CTCAGTGAAAGTCTCCTGCGAGGGTTTTGGAAACACTCTCAGTGAAA GATCCATACACTGGGTGCGACAGGCTCCAGGAAAAGGGCCTGAGTGG ATGGGAGATTATGATCATGAAGATAAAGAAGCAATCTACGCACCGAA GTTCCAGGGCAGACTCACAATAAGCGCGGACATGTCTACAGACATAG CCTCCTTGGAGCTGAACAGCCTGACATCAGAAGACACAGCCGTCTAT TATTGTGCGACAGTGATCGCTGTGGGGGCTTATGACATCTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 79 1250 1250 EVQLVESGAEMKQPGASVKVSCEGFGNTLSERSIHWVRQAPGKGPEWM GDYDHEDKEAIYAPKFQGRLTISADMSTDIASLELNSLTSEDTAVYYCAT VIAVGAYDIWGQGTLVTVSS 79 1251 1251 NTLSERSIH 79 1252 1252 AACACTCTCAGTGAAAGATCCATACAC 79 1253 1253 DYDHEDKEAIYAPKFQG 79 1254 1254 GATTATGATCATGAAGATAAAGAAGCAATCTACGCACCGAAGTTCCA GGGC 79 1255 1255 ATVIAVGAYDI 79 1256 1256 GCGACAGTGATCGCTGTGGGGGCTTATGACATC 79 1257 1257 GAAATTGTATTGACACAGTCTCCATCCTCCCTGTATGCGTCTATAGGG GACAGAGTCACCATCACTTGCCGGACTGGTCAGAGCATTTCCCGGTA TTTGAATTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAACTCCTGA TCTATGCAGCATCCACTTTGCAAAGTGGGGTCCCATCACGTTTCAGTG GCAGTGGCGCTGGGACAGATTTCACTCTCACCATCAGAGGTCTGCTA CCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACATTATCCCC TACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 79 1258 1258 EIVLTQSPSSLYASIGDRVTITCRTGQSISRYLNWYQQKPGKAPKLLIYAA STLQSGVPSRFSGSGAGTDFTLTIRGLLPEDFATYFCQQSYIIPYTFGQGTK VEIK 79 1259 1259 RTGQSISRYLN 79 1260 1260 CGGACTGGTCAGAGCATTTCCCGGTATTTGAAT 79 1261 1261 AASTLQS 79 1262 1262 GCAGCATCCACTTTGCAAAGT 79 1263 1263 QQSYIIPYT 79 1264 1264 CAACAGAGTTACATTATCCCCTACACT 80 1265 1265 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGGTGAAGCCTTCGGA GACCCTGTCCCTCACCTGCGCTGTGTATGGTGGGTCCTTCAGTGGTTA CCAGTGGCACTGGTTCCGCCAGCCCCCAGGGAAGGGTCTGGAGTGGA TTGGGGAAATCAATCATAGTGAAATCACCCACTACAACGCGTCCCTC AAGAGTCGAGTCACCCTATCTATTGACACGTCCAAGAACCAATTCTCC CTGAACCTGACCTCTGTGACCGCCGCGGACACGGCTGTTTATTACTGT GCGAGAGCCTCGAGTGGGAGCTATAACTTCGAATACTGGTTCGACCC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 80 1266 1266 QVQLQQWGAGLVKPSETLSLTCAVYGGSFSGYQWHWFRQPPGKGLEWI GEINHSEITHYNASLKSRVTLSIDTSKNQFSLNLTSVTAADTAVYYCARA SSGSYNFEYWFDPWGQGTLVTVSS 80 1267 1267 GSFSGYQWH 80 1268 1268 GGGTCCTTCAGTGGTTACCAGTGGCAC 80 1269 1269 EINHSEITHYNASLKS 80 1270 1270 GAAATCAATCATAGTGAAATCACCCACTACAACGCGTCCCTCAAGAGT 80 1271 1271 ARASSGSYNFEYWFDP 80 1272 1272 GCGAGAGCCTCGAGTGGGAGCTATAACTTCGAATACTGGTTCGACCCC 80 1273 1273 CAGTCTGTGCTGACGCAGCCGCCCTCGGTGTCCGTGGCCCCAGGAAA GACGGCCTGGCTTACCTGTGGGGGAAACAACATTGGCAGTAAGAGAG TGCACTGGTACCGGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTT TATGATGATTACGACCGGCCCTCAGGGACCCCTGAGCGAGTCTCTGG CTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAG ACGGGGATGAGGGCGACTATTATTGTCAGGTGTGGGATGATCCCAGT GATCATGCGGTGTTCGGCGGCGGGACCAAGCTGACCGTCCTA 80 1274 1274 QSVLTQPPSVSVAPGKTAWLTCGGNNIGSKRVHWYRQKPGQAPVLVVY DDYDRPSGTPERVSGSNSGNTATLTISRVEDGDEGDYYCQVWDDPSDHA VFGGGTKLTVL 80 1275 1275 GGNNIGSKRVH 80 1276 1276 GGGGGAAACAACATTGGCAGTAAGAGAGTGCAC 80 1277 1277 DDYDRPS 80 1278 1278 GATGATTACGACCGGCCCTCA 80 1279 1279 QVWDDPSDHAV 80 1280 1280 CAGGTGTGGGATGATCCCAGTGATCATGCGGTG 81 1281 1281 CAGGTCCAGCTTGTGCAGTCTGGAACTGAGGTTAAGAAGCCTGGGGC CTCAGTGAAGGTCTCCTGCTTGACTTCTGGCTACACCTTTACACACTT TGGTATCAGCTGGGTGCGACAGGCCCCAGGACAAGGGCTTGAGTGGA TGGGATGGTTCAGCGCTTACAATGGTAACACAAAGTATGCACAGAAG TTCCAGGGCAGAATCACCCTCACCATAGACACATCCACGAGCATCGC CTACTTGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTATATT ATTGTGCGAGAGACCCCCCGAGTCTGACAGCAGCTGGTACTCTGGAC TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 81 1282 1282 QVQLVQSGTEVKKPGASVKVSCLTSGYTFTHFGISWVRQAPGQGLEWM GWFSAYNGNTKYAQKFQGRITLTIDTSTSIAYLELRSLRSDDTAVYYCAR DPPSLTAAGTLDYWGQGTLVTVSS 81 1283 1283 YTFTHFGIS 81 1284 1284 TACACCTTTACACACTTTGGTATCAGC 81 1285 1285 WFSAYNGNTKYAQKFQG 81 1286 1286 TGGTTCAGCGCTTACAATGGTAACACAAAGTATGCACAGAAGTTCCA GGGC 81 1287 1287 ARDPPSLTAAGTLDY 81 1288 1288 GCGAGAGACCCCCCGAGTCTGACAGCAGCTGGTACTCTGGACTAC 81 1289 1289 GACATCCGGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGCTCTAATCAAAGCCTCGTATACAGT GATGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATC TCCAAGGCGCCTAATTTATAAGGTTTCTGATCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA GCTACAGACTGGCCCCGGACGTTCGGCCAAGGGACCAAGGTGGAGAT CAAA 81 1290 1290 DIRLTQSPLSLPVTLGQPASISCSSNQSLVYSDGNTYLSWFQQRPGQSPRR LIYKVSDRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATDWP RTFGQGTKVEIK 81 1291 1291 SSNQSLVYSDGNTYLS 81 1292 1292 AGCTCTAATCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAGT 81 1293 1293 KVSDRDS 81 1294 1294 AAGGTTTCTGATCGGGACTCT 81 1295 1295 MQATDWPRT 81 1296 1296 ATGCAAGCTACAGACTGGCCCCGGACG 82 1297 1297 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGG ACTCAGTGAAGGTCTCCTGCAGGGCTTCTGGATACAGCTTCACCGGCC CCTTTTTGCACTGGGTGCGACAGGCCCCTGGACAGCGGCTTGAGCAC ATGGGATGGATCAACCCTAGAAGTGGTGAAACAAAATATGCACAGTC CTTTCTGGGCAGGGTCACCATGACCAGGGACACGTCCATTCGCTCAG CCACCTTGGAATTGAGTAGCCTGAGATCTGACGACACGGCCGTGTAT TATTGTGCGAGAGACCTCTATAGCAGTGGCTGGCTCGACAACTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA 82 1298 1298 EVQLVESGAEVKKPGDSVKVSCRASGYSFTGPFLHWVRQAPGQRLEHM GWINPRSGETKYAQSFLGRVTMTRDTSIRSATLELSSLRSDDTAVYYCAR DLYSSGWLDNWGQGTLVTVSS 82 1299 1299 YSFTGPFLH 82 1300 1300 TACAGCTTCACCGGCCCCTTTTTGCAC 82 1301 1301 WINPRSGETKYAQSFLG 82 1302 1302 TGGATCAACCCTAGAAGTGGTGAAACAAAATATGCACAGTCCTTTCT GGGC 82 1303 1303 ARDLYSSGWLDN 82 1304 1304 GCGAGAGACCTCTATAGCAGTGGCTGGCTCGACAAC 82 1305 1305 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGG GGAAAGGGCCACCCTCTCCTGCAGGGCCAGTCAGGGTCTTAGCAGCA ACTTAGCCTGGTACCAGCACAAACCTGGCCAGGCTCCCAGGCTCCTC GTCTATGGTGTTGCCACCAGGGCCACTGGTGTCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCA GTCTGACGATTTTGCACTTTATTACTGTCATCAGTATAATGACTGGCC CTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 82 1306 1306 ETTLTQSPATLSVSPGERATLSCRASQGLSSNLAWYQHKPGQAPRLLVY GVATRATGVPARFSGSGSGTEFTLTISSLQSDDFALYYCHQYNDWPYTF GQGTKLEIK 82 1307 1307 RASQGLSSNLA 82 1308 1308 AGGGCCAGTCAGGGTCTTAGCAGCAACTTAGCC 82 1309 1309 GVATRAT 82 1310 1310 GGTGTTGCCACCAGGGCCACT 82 1311 1311 HQYNDWPYT 82 1312 1312 CATCAGTATAATGACTGGCCCTACACT 83 1313 1313 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCTAAGACTCTCATGTGCAGCCTCTGGATTCATCTTCCGCAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCG ACACCCGTGCAAGGCAGATTCTCCATCTCAAGAGATGATTCTAGAAA CACGCTGTATCTGCAAATGAACAGCCTGGAAACCGACGACACAGCCG TGTATTACTGTTCCACAGGCCCACCCTACTCTTACTTTGATAGTAGTG GTTATTCGGTCGTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 83 1314 1314 EVQLVESGGGLVKPGGSLRLSCAASGFIFRNAWMSWVRQAPGKGLEWV GRIKRTSEGGSVDYATPVQGRFSISRDDSRNTLYLQMNSLETDDTAVYY CSTGPPYSYFDSSGYSVVDYWGQGTLVTVSS 83 1315 1315 FIFRNAWMS 83 1316 1316 TTCATCTTCCGCAACGCCTGGATGAGC 83 1317 1317 RIKRTSEGGSVDYATPVQG 83 1318 1318 CGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCGACACC CGTGCAAGGC 83 1319 1319 STGPPYSYFDSSGYSVVDY 83 1320 1320 TCCACAGGCCCACCCTACTCTTACTTTGATAGTAGTGGTTATTCGGTC GTGGACTAC 83 1321 1321 CAGTCTGTGTTGACGCAGCCGCCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGCAAGCAGCTCCAACATCGGAGATA ATTATTTCTACTGGTACCAACAACTCCCAGGAAAGGCCCCCACACTCC TCATGTATGGTAGTGATCAGCGGTCCTCAGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCACCTCTGCCTCCCTGGCCATCAGTGGGCTCC GGTCCGAGGATGAAGCTGATTATTATTGTGCAGCTTGGGATGACAGC CTGAGTGGTCCGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 83 1322 1322 QSVLTQPPSASGTPGQRVTISCSASSSNIGDNYFYWYQQLPGKAPTLLMY GSDQRSSGVPDRFSGSQSGTSASLAISGLRSEDEADYYCAAWDDSLSGPV FGGGTKLTVL 83 1323 1323 SASSSNIGDNYFY 83 1324 1324 TCTGCAAGCAGCTCCAACATCGGAGATAATTATTTCTAC 83 1325 1325 GSDQRSS 83 1326 1326 GGTAGTGATCAGCGGTCCTCA 83 1327 1327 AAWDDSLSGPV 83 1328 1328 GCAGCTTGGGATGACAGCCTGAGTGGTCCGGTG 84 1329 1329 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG GTCCCTGAGACTCTCGTGTGCAGCCTCTGGATTCTCCTTCAGTGACTA CAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG GTTTCATATATTACTCCTAGTAGTAGAAATAAATTCTATGCAGACTCT GTGAGGGGCCGATTCACCATCTCCAGAGACAATGCCGAGAATTCACT GTATCTGCAAATGAACAGCCTGAGAGTCGAAGACACGGCTGTTTATT ACTGTGTCAGAAGTTTGCATTGGGGCGCCGCGATCGAGAGATGGGAC GTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 84 1330 1330 EVQLVESGGGLVQPGGSLRLSCAASGFSFSDYSMNWVRQAPGKGLEWV SYITPSSRNKFYADSVRGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVR SLHWGAAIERWDVWGQGTTVTVSS 84 1331 1331 FSFSDYSMN 84 1332 1332 TTCTCCTTCAGTGACTACAGCATGAAC 84 1333 1333 YITPSSRNKFYADSVRG 84 1334 1334 TATATTACTCCTAGTAGTAGAAATAAATTCTATGCAGACTCTGTGAGG GGC 84 1335 1335 VRSLHWGAAIERWDV 84 1336 1336 GTCAGAAGTTTGCATTGGGGCGCCGCGATCGAGAGATGGGACGTC 84 1337 1337 GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCGTTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCAG CTTCTTTGCCTGGTACCAGCAGACACCTGGCCAGGCCCCCAGACTCCT CATGTATGCTACATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGAGTG GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTCTGGCAGTTCA CCGTACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 84 1338 1338 EIVLTQSPGTLSLSPGERATLSCRASQSISSSFFAWYQQTPGQAPRLLMYA TSSRATGIPDRFSGSGSGTDFTLTISRVEPEDFAVYYCQQSGSSPYTFGQG TKVEIK 84 1339 1339 RASQSISSSFFA 84 1340 1340 AGGGCCAGTCAGAGTATTAGCAGCAGCTTCTTTGCC 84 1341 1341 ATSSRAT 84 1342 1342 GCTACATCCAGCAGGGCCACT 84 1343 1343 QQSGSSPYT 84 1344 1344 CAGCAGTCTGGCAGTTCACCGTACACT 85 1345 1345 GAGGTGCAGCTGTTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTCAGTGACCA TGCTATGTACTGGGTCCGCCAGGCTCCAGGCAAAGGGCTAGAGTGGG TGGCACTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCCG TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAGATGAACAGCCTGAGAGCTGAGGACACGGCTGTCTATTA CTGTGCGAGAGATCAATGGCTGGTTCCTGACTACTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA 85 1346 1346 EVQLLESGGGVVQPGRSLRLSCTASGFTFSDHAMYWVRQAPGKGLEWV ALISFDGRNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA RDQWLVPDYWGQGTLVTVSS 85 1347 1347 FTFSDHAMY 85 1348 1348 TTCACCTTCAGTGACCATGCTATGTAC 85 1349 1349 LISFDGRNIYYADSVKG 85 1350 1350 CTTATATCATTTGATGGAAGGAATATATACTACGCAGACTCCGTGAA GGGC 85 1351 1351 ARDQWLVPDY 85 1352 1352 GCGAGAGATCAATGGCTGGTTCCTGACTAC 85 1353 1353 CAGTCTGTTCTGATTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTATGTCTCCTGGTACCAACAGCACCCAGGCAACGCCCCCAAACT CATGATTTATGAAGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT CTCTGGCTTCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA GCAACAGTGTCTTCGGAACTGGCACCCAGCTGACCGTCCTC 85 1354 1354 QSVLIQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGNAPKLMI YEVSKRPSGVPDRFSGFKSGNTASLTVSGLQAEDEADYYCSSYAGSNSV FGTGTQLTVL 85 1355 1355 TGTSSDVGGYNYVS 85 1356 1356 ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCC 85 1357 1357 EVSKRPS 85 1358 1358 GAAGTCAGTAAGCGGCCCTCA 85 1359 1359 SSYAGSNSV 85 1360 1360 AGCTCATATGCAGGCAGCAACAGTGTC 86 1361 1361 GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTAGTTAGGCCTTCACA GACCCTGTCCATAAAGTGCAGTGTCTCTGGCGGCTCCATCAATAGAG GTGCTTACTTCTGGACCTGGATCCGCCAGCGCCCAGGGAAGGGCCTG GAGTGGATTGGGTCCATCCATGACACCGGCAGCTACTACAACCCGTC CCTCAAGACACGAGTTTCCATCTCCGGGGACACGTCTAAAAACCTCTT CACCCTGGAGTTGACCTCGCTGACTGCCGCGGACACGGCCGTGTATT ACTGTGCGAGGGGGCGTGGATACAGCTATGGCTGGCGTTACTTTGAC TCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 86 1362 1362 EVQLVESGPGLVRPSQTLSIKCSVSGGSINRGAYFWTWIRQRPGKGLEWI GSIHDTGSYYNPSLKTRVSISGDTSKNLFTLELTSLTAADTAVYYCARGR GYSYGWRYFDSWGQGTLVTVSS 86 1363 1363 GSINRGAYFWT 86 1364 1364 GGCTCCATCAATAGAGGTGCTTACTTCTGGACC 86 1365 1365 SIHDTGSYYNPSLKT 86 1366 1366 TCCATCCATGACACCGGCAGCTACTACAACCCGTCCCTCAAGACA 86 1367 1367 ARGRGYSYGWRYFDS 86 1368 1368 GCGAGGGGGCGTGGATACAGCTATGGCTGGCGTTACTTTGACTCC 86 1369 1369 TCCTATGTGCTGACTCAGCCACCCTCGGTGTCAGTGTCTCCAGGACAG ACGGCCAGGATCACCTGCTCTGGCGATGCATTCCCAAGACAATATTCT TATTGGTACCAGCAGAAGGCAGGCCAGCCCCCTGTGTTGGTAATATT GAAAGACTCTGAGAGGCCCTCAGGGATCCCTGCGCGATTCTCTGGCT CCACCTCAGGGACAACAGTCACCTTGACCATCACTGGAGTCCAGGCA GAAGACGAGGCAGACTATTACTGTCAATCATCGGACAGCAGTGGAAA TTATGTGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 86 1370 1370 SYVLTQPPSVSVSPGQTARITCSGDAFPRQYSYWYQQKAGQPPVLVILKD SERPSGIPARFSGSTSGTTVTLTITGVQAEDEADYYCQSSDSSGNYVVFGG GTKLTVL 86 1371 1371 SGDAFPRQYSY 86 1372 1372 TCTGGCGATGCATTCCCAAGACAATATTCTTAT 86 1373 1373 KDSERPS 86 1374 1374 AAAGACTCTGAGAGGCCCTCA 86 1375 1375 QSSDSSGNYVV 86 1376 1376 CAATCATCGGACAGCAGTGGAAATTATGTGGTG 87 1377 1377 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAATTGAAGAGGCCTGGGTC ATCGGTGAAGGTCTCCTGCAAGGCTTCAGGGGTCTATTTGACCTCGGT TGCTGTCAACTGGGTGCGACAGGTCCCTGGACATGGGTTCGAGTGGA TGGGTGGGATACTCACTGGCTTTGGTAAAGTCAGACACGCCCAGGCC TTTGAGAACCGTGCCACGCTCACCGCGGACGCGTCGACCAACACAGC CTACTTGGAGTTGAGCGGACTTCAAGCTGAAGACACGGCCGCCTATT ATTGTGCGATAATCGACCCCCAAGATTGTACGGCCGCCAGCTGCTTTT GGGTCAACTGGCTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTC TCCTCA 87 1378 1378 QVQLVQSGAELKRPGSSVKVSCKASGVYLTSVAVNWVRQVPGHGFEW MGGILTGFGKVRHAQAFENRATLTADASTNTAYLELSGLQAEDTAAYY CAIIDPQDCTAASCFWVNWLDPWGQGTLVTVSS 87 1379 1379 VYLTSVAVN 87 1380 1380 GTCTATTTGACCTCGGTTGCTGTCAAC 87 1381 1381 GILTGFGKVRHAQAFEN 87 1382 1382 GGGATACTCACTGGCTTTGGTAAAGTCAGACACGCCCAGGCCTTTGA GAAC 87 1383 1383 AIIDPQDCTAASCFWVNWLDP 87 1384 1384 GCGATAATCGACCCCCAAGATTGTACGGCCGCCAGCTGCTTTTGGGTC AACTGGCTCGACCCC 87 1385 1385 GAAATTGTATTGACACAGTCTCCAGGCACCCTGACCGTGTCTCCAGG GGAGAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTCTTAGTA GTCACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTC CTCATCTATGCTGCATCCAGTAGGGCCACTGACGTCCCAGACAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACT GGAGCCTCAAGATTTTGCAGTCTATTACTGTCAGCAGTATGGTTCCTC TCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 87 1386 1386 EIVLTQSPGTLTVSPGERATLSCRASQSVLSSHLAWYQQKPGQAPRLLIY AASSRATDVPDRFSGSGSGTDFTLTISRLEPQDFAVYYCQQYGSSPITFGQ GTRLEIK 87 1387 1387 RASQSVLSSHLA 87 1388 1388 AGGGCCAGTCAGAGTGTTCTTAGTAGTCACTTAGCC 87 1389 1389 AASSRAT 87 1390 1390 GCTGCATCCAGTAGGGCCACT 87 1391 1391 QQYGSSPIT 87 1392 1392 CAGCAGTATGGTTCCTCTCCGATCACC 88 1393 1393 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGTAAGGTTGCCGGAGGTTCCTTCTCCAATTA TGCAATCGCCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGAGGGATCATACCTGCCTTTAATAGAGCAATGTATGCACGGAAG TTCCAAGACAGAGTCACAATTACCGCGTACGCATCAACGACCACTGC CTACCTGGACATTACCGGCCTCAGATCTGAGGACACGGCCCTTTATTA TTGTGCGAGGCCTGCTGGAGACTTTGGGGATTTAAAGTGGGTACGAT CGCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 88 1394 1394 QVQLVQSGAEVKKPGSSVKVSCKVAGGSFSNYAIAWLRQAPGQGLEW MGGIIPAFNRAMYARKFQDRVTITAYASTTTAYLDITGLRSEDTALYYCA RPAGDFGDLKWVRSPFDYWGQGTLVTVSS 88 1395 1395 GSFSNYAIA 88 1396 1396 GGTTCCTTCTCCAATTATGCAATCGCC 88 1397 1397 GIIPAFNRAMYARKFQD 88 1398 1398 GGGATCATACCTGCCTTTAATAGAGCAATGTATGCACGGAAGTTCCA AGAC 88 1399 1399 ARPAGDFGDLKWVRSPFDY 88 1400 1400 GCGAGGCCTGCTGGAGACTTTGGGGATTTAAAGTGGGTACGATCGCC TTTTGACTAC 88 1401 1401 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTGTGTCTCCAGG GGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGGAAGTTGGCATCA ACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTC ATATATGGTGCATCCACCAGGGCCACTGATGTCCCAGCCAGGTTCAG TGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGC AGTCTGAAGATTTTGCAGTTTATTATTGTCAGGAGTATAATGACTGGC CTCCCCAGCTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 88 1402 1402 ETTLTQSPGTLSVSPGERATLSCRASQEVGINLAWYQQKPGQAPRLLIYG ASTRATDVPARFSGSGSGTEFTLTISSLQSEDFAVYYCQEYNDWPPQLTF GPGTKVDIK 88 1403 1403 RASQEVGINLA 88 1404 1404 AGGGCCAGTCAGGAAGTTGGCATCAACTTAGCC 88 1405 1405 GASTRAT 88 1406 1406 GGTGCATCCACCAGGGCCACT 88 1407 1407 QEYNDWPPQLT 88 1408 1408 CAGGAGTATAATGACTGGCCTCCCCAGCTCACT 89 1409 1409 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCTAAGACTCTCATGTGCAGCCTCTGGATTCATCTTCCGCAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCG ACACCCGTGCAAGGCAGATTCTCCATCTCAAGAGATGATTCTAGAAA CACGCTGTATCTGCAAATGAACAGCCTGGAAACCGACGACACAGCCG TGTATTACTGTTCCACAGGCCCACCCTATTCTTACTTTGATAGTAGTG GTTATTCGGTCGTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 89 1410 1410 EVQLVESGGGLVKPGGSLRLSCAASGFIFRNAWMSWVRQAPGKGLEWV GRIKRTSEGGSVDYATPVQGRFSISRDDSRNTLYLQMNSLETDDTAVYY CSTGPPYSYFDSSGYSVVDYWGQGTLVTVSS 89 1411 1411 FIFRNAWMS 89 1412 1412 TTCATCTTCCGCAACGCCTGGATGAGC 89 1413 1413 RIKRTSEGGSVDYATPVQG 89 1414 1414 CGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCGACACC CGTGCAAGGC 89 1415 1415 STGPPYSYFDSSGYSVVDY 89 1416 1416 TCCACAGGCCCACCCTATTCTTACTTTGATAGTAGTGGTTATTCGGTC GTGGACTAC 89 1417 1417 CAGTCTGTCGTGACGCAGCCGCCCTCAGTGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCCTGCACTGGGAGCTCCTCCAACATCGGGACAC CTTTTGATGTACACTGGTACCAGCAGATTCCAGAGACAGCCCCCAAA CTCATCATATCTGGTGGTTTCAGTCGGCCCTCAGGGGTCCCTGACCGA TTCTCTGGCTCCCAGTCTGGCACCTCTGCCTCCCTGGCCATCAGTGGG CTCCGGTCCGAGGATGAAGGTGATTATTATTGTGCAGCTTGGGATGA CAGCCTGAGTGGTCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCC TA 89 1418 1418 QSVVTQPPSVSGTPGQRVTISCTGSSSNIGTPFDVHWYQQIPETAPKLIISG GFSRPSGVPDRFSGSQSGTSASLAISGLRSEDEGDYYCAAWDDSLSGPVF GGGTKLTVL 89 1419 1419 TGSSSNIGTPFDVH 89 1420 1420 ACTGGGAGCTCCTCCAACATCGGGACACCTTTTGATGTACAC 89 1421 1421 GGFSRPS 89 1422 1422 GGTGGTTTCAGTCGGCCCTCA 89 1423 1423 AAWDDSLSGPV 89 1424 1424 GCAGCTTGGGATGACAGCCTGAGTGGTCCGGTG 90 1425 1425 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGTAAGGTTGTCGGAGGCAGTTTCAGCAACT ATGGGATTGGCTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTGG ATGGGAGGGATCATCCCTGCCTTTAAGACAGCAAAATATGCAAAGAA GTTCCAGGACAGAGTCACAATTACCGCGGACGAATCTTCGAGCACTG CCTACATGGAGGTGAGAGGCCTCAGACCTGACGACACGGCCCTGTAT TATTGTGCGAGGCCTGAAGGAGACTTTGGAGATTTGAAGTGGGTACG ATCGCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 90 1426 1426 QVQLVQSGAEVKKPGSSVKVSCKVVGGSFSNYGIGWVRQAPGQGPEW MGGIIPAFKTAKYAKKFQDRVTITADESSSTAYMEVRGLRPDDTALYYC ARPEGDFGDLKWVRSPFDYWGQGTLVTVSS 90 1427 1427 GSFSNYGIG 90 1428 1428 GGCAGTTTCAGCAACTATGGGATTGGC 90 1429 1429 GIIPAFKTAKYAKKFQD 90 1430 1430 GGGATCATCCCTGCCTTTAAGACAGCAAAATATGCAAAGAAGTTCCA GGAC 90 1431 1431 ARPEGDFGDLKWVRSPFDY 90 1432 1432 GCGAGGCCTGAAGGAGACTTTGGAGATTTGAAGTGGGTACGATCGCC TTTTGACTAC 90 1433 1433 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGG GGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGGATGTTAGCATCA ACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTC ATCTATGGTGCATCCACCAGGGCCACTGATGTCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCA GTCTGAAGATTTTGCATTTTATTATTGTCAGGAGTATAATGACTGGCC TCCCCAGCTCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 90 1434 1434 ETTLTQSPATLSVSPGERVTLSCRASQDVSINLAWYQQKPGQAPRLLIYG ASTRATDVPARFSGSGSGTDFTLTISSLQSEDFAFYYCQEYNDWPPQLTF GPGTKVEIK 90 1435 1435 RASQDVSINLA 90 1436 1436 AGGGCCAGTCAGGATGTTAGCATCAACTTAGCC 90 1437 1437 GASTRAT 90 1438 1438 GGTGCATCCACCAGGGCCACT 90 1439 1439 QEYNDWPPQLT 90 1440 1440 CAGGAGTATAATGACTGGCCTCCCCAGCTCACT 91 1441 1441 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC ATCGGTGAAGGTCTCCTGCAAGGCCTCAGGAGTCATTTTGACCAGCG TTGCTGTCAGCTGGGTGCGGCAGGCCCCTGGAAAAGGCTTTGAGTGG ATGGGAGGGATTCTTCCTGGCTTTAATAAAGTCAGACACGCCCAGGA TTTTGAGAACAGAGCCACTCACACCGCGGACGCATCTACGAACACAG TCTACATGGAGTTGAGCGGACTGAAATCTGAGGACACGGCCGTCTAT TACTGTGCGATAATCGACCCCCAAGATTGTACTCGTGCCAGTTGCTTT TGGGTCAACTGGCTCGCCCCCTGGGGCCAGGGAACCCTGGTCACCGT CTCCTCA 91 1442 1442 QVQLVQSGAEVKKPGSSVKVSCKASGVILTSVAVSWVRQAPGKGFEWM GGILPGFNKVRHAQDFENRATHTADASTNTVYMELSGLKSEDTAVYYC AIIDPQDCTRASCFWVNWLAPWGQGTLVTVSS 91 1443 1443 VILTSVAVS 91 1444 1444 GTCATTTTGACCAGCGTTGCTGTCAGC 91 1445 1445 GILPGFNKVRHAQDFEN 91 1446 1446 GGGATTCTTCCTGGCTTTAATAAAGTCAGACACGCCCAGGATTTTGAG AAC 91 1447 1447 AIIDPQDCTRASCFWVNWLAP 91 1448 1448 GCGATAATCGACCCCCAAGATTGTACTCGTGCCAGTTGCTTTTGGGTC AACTGGCTCGCCCCC 91 1449 1449 GAAACGACACTCACGCAGTCTCCCGGCACCCTGACCTTGTCTCCAGG GGAGAGAGCCACCCTGTCCTGCAGGGCCAGTCAGAGTGTTCCTAGCA GGAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTC ATCATCTATGCTGCATCCAATAGGGCCACTGACATCCCAGACAGGTTC AGTGGCAGTGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGACT GGAGCCTCAAGATTTTGCAGTGTATTACTGTCAGCAGTATGAAACCTC TCCGATCACCTTCGGCCAAGGGACCAAAGTGGATATCAAA 91 1450 1450 ETTLTQSPGTLTLSPGERATLSCRASQSVPSRNLAWYQQKPGQAPRLIIYA ASNRATDIPDRFSGSGSGTDFTLTISRLEPQDFAVYYCQQYETSPITFGQG TKVDIK 91 1451 1451 RASQSVPSRNLA 91 1452 1452 AGGGCCAGTCAGAGTGTTCCTAGCAGGAACTTAGCC 91 1453 1453 AASNRAT 91 1454 1454 GCTGCATCCAATAGGGCCACT 91 1455 1455 QQYETSPIT 91 1456 1456 CAGCAGTATGAAACCTCTCCGATCACC 92 1457 1457 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCTAAGACTCTCATGTGCAGCCTCTGGATTCATCTTCCGCAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCG ACACCCGTGCAAGGCAGATTCTCCATCTCAAGAGATGATTCTAGAAA GACGCTGTATCTGCAAATGAACAGCCTGGAAACCGACGACACAGCCG TGTATTACTGTTCCACAGGCCCACCCTATTCTTACTTTGATAGTAGTG GTTATTCGGTCGTGGACTACTGGGGCCTGGGAACCCTGGTCACCGTCT CCTCA 92 1458 1458 EVQLVESGGGLVKPGGSLRLSCAASGFIFRNAWMSWVRQAPGKGLEWV GRIKRTSEGGSVDYATPVQGRFSISRDDSRKTLYLQMNSLETDDTAVYY CSTGPPYSYFDSSGYSVVDYWGLGTLVTVSS 92 1459 1459 FIFRNAWMS 92 1460 1460 TTCATCTTCCGCAACGCCTGGATGAGC 92 1461 1461 RIKRTSEGGSVDYATPVQG 92 1462 1462 CGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCGACACC CGTGCAAGGC 92 1463 1463 STGPPYSYFDSSGYSVVDY 92 1464 1464 TCCACAGGCCCACCCTATTCTTACTTTGATAGTAGTGGTTATTCGGTC GTGGACTAC 92 1465 1465 TCCTATGAGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGCAAGCAGCTCCAACATCGGAGATA ATTATTTCTACTGGTACCAACAACTCCCAGGAAAGGCCCCCACACTCC TCATGTATGGTAGTGATCAACGGTCCTCAGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCACCTCTGCCTCCCTGGCCATCAGTGGGCTCC GGTCCGAGGATGAAGCTGATTATTATTGTGCAGCTTGGGATGACAGC CTGAGTGGTCCGGTGTTCGGCGGAGGCACCCAGCTGACCGTCCTC 92 1466 1466 SYELTQPPSASGTPGQRVTISCSASSSNIGDNYFYWYQQLPGKAPTLLMY GSDQRSSGVPDRFSGSQSGTSASLAISGLRSEDEADYYCAAWDDSLSGPV FGGGTQLTVL 92 1467 1467 SASSSNIGDNYFY 92 1468 1468 TCTGCAAGCAGCTCCAACATCGGAGATAATTATTTCTAC 92 1469 1469 GSDQRSS 92 1470 1470 GGTAGTGATCAACGGTCCTCA 92 1471 1471 AAWDDSLSGPV 92 1472 1472 GCAGCTTGGGATGACAGCCTGAGTGGTCCGGTG 93 1473 1473 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGATAATCTCCTGCAAGGCATCTGGAGGCACCTTCAGAAACT ACGGTTTCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGG TTGGGAGGGATCATCCCTATGTTTGAGACAGTCAGATATGCACAGAA GTTCCAGGGAAGAGTCACAATCACCGCGGACGAAAACACCAACACA GCCTTCCTGGCGGTGAGCAGCCTGCGATCTGAAGACACGGGCGTCTA TTTTTGTGCGCGAGACCTCCAGACGGGGATTATGAGCAGCGTGAGGT CGGAATATAGGGGCTTTATGGACCCCTGGGGCCAGGGAACCCTGGTC ACCGTCTCCTCA 93 1474 1474 QVQLVQSGAEVKKPGSSVIISCKASGGTFRNYGFTWVRQAPGQGLEWLG GIIPMFETVRYAQKFQGRVTITADENTNTAFLAVSSLRSEDTGVYFCARD LQTGIMSSVRSEYRGFMDPWGQGTLVTVSS 93 1475 1475 GTFRNYGFT 93 1476 1476 GGCACCTTCAGAAACTACGGTTTCACC 93 1477 1477 GIIPMFETVRYAQKFQG 93 1478 1478 GGGATCATCCCTATGTTTGAGACAGTCAGATATGCACAGAAGTTCCA GGGA 93 1479 1479 ARDLQTGIMSSVRSEYRGFMDP 93 1480 1480 GCGCGAGACCTCCAGACGGGGATTATGAGCAGCGTGAGGTCGGAATA TAGGGGCTTTATGGACCCC 93 1481 1481 CAGTCTGTGCTGACGCAGCCGCCCTCGGTGTCTGGAGCCCCCCGGCA GAGGGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACATCGGAACTA ATGCTGTAAACTGGTACCAACAGCTCCCAGGAAAGTCTCCCAAAGTC CTCATCTACTATGATGAGCTGGTGCCCTCAGGGGTCTCTGACCGATTC TCTGGCTCCAGGTCTGGCACCTCAGCCTCCCTGGCCATAAGTGGACTC CGGTCTGAGGATGAGGCTTACTATTACTGTGCAGCTTGGGATGACAG TCTGAATGGTTGGGTGTTCGGCGGAGGCACCCAGCTCACCGTCCTA 93 1482 1482 QSVLTQPPSVSGAPRQRVTISCSGSSSNIGTNAVNWYQQLPGKSPKVLIY YDELVPSGVSDRFSGSRSGTSASLAISGLRSEDEAYYYCAAWDDSLNGW VFGGGTQLTVL 93 1483 1483 SGSSSNIGTNAVN 93 1484 1484 TCTGGAAGCAGCTCCAACATCGGAACTAATGCTGTAAAC 93 1485 1485 YDELVPS 93 1486 1486 TATGATGAGCTGGTGCCCTCA 93 1487 1487 AAWDDSLNGWV 93 1488 1488 GCAGCTTGGGATGACAGTCTGAATGGTTGGGTG 94 1489 1489 GAGGTGCAGCTGGTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGA GGTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACGTTCAGTAACT TTGGGATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGG GTGGCAGCTATTTCATACGATGGAAGAAAAAGATTCCAGGCAGACTC CGTGAAGGGCCGATTCACCATCTCCAGAGACAACTTGAAGAACACGC TGAATCTCCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTGTAT TACTGTGCGAAATCGTCTAGACTTTTGGACTGGTTATACAATATGGAC TTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 94 1490 1490 EVQLVESGGGVVQPGRSLRLSCAVSGFTFSNFGMHWVRQAPGKGLEWV AAISYDGRKRFQADSVKGRFTISRDNLKNTLNLQMNSLKTEDTAVYYCA KSSRLLDWLYNMDFWGQGTTVTVSS 94 1491 1491 FTFSNFGMH 94 1492 1492 TTCACGTTCAGTAACTTTGGGATGCAC 94 1493 1493 AISYDGRKRFQADSVKG 94 1494 1494 GCTATTTCATACGATGGAAGAAAAAGATTCCAGGCAGACTCCGTGAA GGGC 94 1495 1495 AKSSRLLDWLYNMDF 94 1496 1496 GCGAAATCGTCTAGACTTTTGGACTGGTTATACAATATGGACTTC 94 1497 1497 TCCTATGTGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAA GACGGCCAGGATTACCTGTGGGGGAAACATCCTTGGGAGTTCAAGTG TCCACTGGTTCCAGCAGAAGGCAGGCCAGGCCCCTGTCCTGGTCATCT ATTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT CCCATTCTGGGGACACGGCCACCCTGACCATCAGCAGGGTCGAAGTC GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAATAGTAATTC CCAGGGGGTCTTCGGCGGAGGCACCCAGCTGACCGTCCTC 94 1498 1498 SYVLTQPPSVSVAPGKTARITCGGNILGSSSVHWFQQKAGQAPVLVIYYD SDRPSGIPERFSGSHSGDTATLTISRVEVGDEADYYCQVWDNSNSQGVFG GGTQLTVL 94 1499 1499 GGNILGSSSVH 94 1500 1500 GGGGGAAACATCCTTGGGAGTTCAAGTGTCCAC 94 1501 1501 YDSDRPS 94 1502 1502 TATGATAGCGACCGGCCCTCA 94 1503 1503 QVWDNSNSQGV 94 1504 1504 CAGGTGTGGGATAATAGTAATTCCCAGGGGGTC 95 1505 1505 CAGGTGCAGCTACAGCAGTGGGGCCCAGGACTGGTGAAGCCGTCACA GACCCTGTCCCTCACCTGCAGTGTCTCTGGTGCCTCAGTCAAAATAGG TTCTAATTTCTGGACGTGGATCCGCCAGCGCCCAGGGAAGGGCCTGG AGTGGATTGGGGCCATCCATGACACTGGCACCACCTACTACAACCCG TCCCTTGAGCCTCAAGTAATCATTTCAACTGACACGTCTCAGAACCAA TTCTCCCTGAGGCTGACCTCTGTGACTGCCGCGGACACGGCCGTTTAC TACTGTGCGAGGGGGCGTGGATACACCTATGGATGGCGTTACTTTGA CTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 95 1506 1506 QVQLQQWGPGLVKPSQTLSLTCSVSGASVKIGSNFWTWIRQRPGKGLE WIGAIHDTGTTYYNPSLEPQVIISTDTSQNQFSLRLTSVTAADTAVYYCA RGRGYTYGWRYFDYWGQGTLVTVSS 95 1507 1507 ASVKIGSNFWT 95 1508 1508 GCCTCAGTCAAAATAGGTTCTAATTTCTGGACG 95 1509 1509 AIHDTGTTYYNPSLEP 95 1510 1510 GCCATCCATGACACTGGCACCACCTACTACAACCCGTCCCTTGAGCCT 95 1511 1511 ARGRGYTYGWRYFDY 95 1512 1512 GCGAGGGGGCGTGGATACACCTATGGATGGCGTTACTTTGACTAC 95 1513 1513 TCCTATGTGCTGACTCAGCCACCCTCGGTGTCAGTGTCCCCAGGACAG ACGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAAGCAATATGC CTTTTGGTATCAGCACAAGGCAGGACAGGCCCCTGTGTTGGTCATAA AAAAAGACACTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGC TCCATCTCAGGGACAACAGCCACTTTGATCATCAGTGGAGTCCAGGC AGAAGACGAGGCTGACTATTACTGTCAATCTTCAGACAGTAGTGGTA ATGTTGTCTTATTCGGCGGAGGCACCCAGCTGACCGTCCTC 95 1514 1514 SYVLTQPPSVSVSPGQTARITCSGDALPKQYAFWYQHKAGQAPVLVIKK DTERPSGIPERFSGSISGTTATLIISGVQAEDEADYYCQSSDSSGNVVLFGG GTQLTVL 95 1515 1515 SGDALPKQYAF 95 1516 1516 TCTGGAGATGCATTGCCAAAGCAATATGCCTTT 95 1517 1517 KDTERPS 95 1518 1518 AAAGACACTGAGAGGCCCTCA 95 1519 1519 QSSDSSGNVVL 95 1520 1520 CAATCTTCAGACAGTAGTGGTAATGTTGTCTTA 96 1521 1521 CAGGTGCAGCTGGTGCAATCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCAGCTTCAGTAGTTA TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG TGGCAGCTATATTTTATCATGAAATTAAGGACTATTATGCAGACTCCG TGAACGGCCGATTCAGCATCTCCAGAGACAATTCCAAGAACACCCTG TATCTGGAAATGTACAGCCTGAAGGTCGAGGACACGGCTGTGTATTA TTGTGCGAGAGATAGTGGGACCCTCACAGGACTCCCGCATGATGCCT TTGATATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 96 1522 1522 QVQLVQSGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGKGLEW VAAIFYHEIKDYYADSVNGRFSISRDNSKNTLYLEMYSLKVEDTAVYYC ARDSGTLTGLPHDAFDIWGQGTTVTVSS 96 1523 1523 FSFSSYGMH 96 1524 1524 TTCAGCTTCAGTAGTTATGGCATGCAC 96 1525 1525 AIFYHEIKDYYADSVNG 96 1526 1526 GCTATATTTTATCATGAAATTAAGGACTATTATGCAGACTCCGTGAAC GGC 96 1527 1527 ARDSGTLTGLPHDAFDI 96 1528 1528 GCGAGAGATAGTGGGACCCTCACAGGACTCCCGCATGATGCCTTTGA TATC 96 1529 1529 GACATCCAGATGACCCAGTCTCCTTCCACCCTGAGTGCATCTTTAGGA GGCAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTGTTACTAACAG GTTGGCCTGGTATCAACACAAACCAGGGAAAGCCCCTAACCTCCTGA TCTATAAGGCGTCTACTTTAGAAATCGGGGTCCCATCAAGGTTCAGCG GCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG CCTGATGATTTTGCGACTTATTACTGCCAACAGTATAGTAGTTATTCG TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 96 1530 1530 DIQMTQSPSTLSASLGGRVTITCRASQSVTNRLAWYQHKPGKAPNLLIYK ASTLEIGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYSSYSWTFGQG TKVEIK 96 1531 1531 RASQSVTNRLA 96 1532 1532 CGGGCCAGTCAGAGTGTTACTAACAGGTTGGCC 96 1533 1533 KASTLEI 96 1534 1534 AAGGCGTCTACTTTAGAAATC 96 1535 1535 QQYSSYSWT 96 1536 1536 CAACAGTATAGTAGTTATTCGTGGACG 97 1537 1537 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGG GTCCCTAAGACTCTCATGTGCAGCCTCTGGATTCATCTTCCGCAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCG ACACCCGTGCAAGGCAGATTCTCCATCTCAAGAGATGATTCTAGAAA GACGCTGTATCTGCAAATGAACAGCCTGGAAACCGACGACACAGCCG TGTATTACTGTTCCACAGGCCCACCCTATTCTTACTTTGATAGTAGTG GTTATTCGGTCGTGGACTACTGGGGCCTGGGAACCCTGGTCACCGTCT CCTCA 97 1538 1538 EVQLVESGGGLVKPGGSLRLSCAASGFIFRNAWMSWVRQAPGKGLEWV GRIKRTSEGGSVDYATPVQGRFSISRDDSRKTLYLQMNSLETDDTAVYY CSTGPPYSYFDSSGYSVVDYWGLGTLVTVSS 97 1539 1539 FIFRNAWMS 97 1540 1540 TTCATCTTCCGCAACGCCTGGATGAGC 97 1541 1541 RIKRTSEGGSVDYATPVQG 97 1542 1542 CGGATTAAAAGGACAAGTGAAGGTGGGTCAGTCGACTACGCGACACC CGTGCAAGGC 97 1543 1543 STGPPYSYFDSSGYSVVDY 97 1544 1544 TCCACAGGCCCACCCTATTCTTACTTTGATAGTAGTGGTTATTCGGTC GTGGACTAC 97 1545 1545 CAGCCAGTGCTGACTCAGCCCCCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGCAAGCAGCTCCAACATCGGAGATA ATTATTTCTACTGGTACCAACAACTCCCAGGAAAGGCCCCCACACTCC TCATGTATGGTAGTGATCAACGGTCCTCAGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCACCTCTGCCTCCCTGGCCATCAGTGGGCTCC GGTCCGAGGATGAAGCTGATTATTATTGTGCAGCTTGGGATGACAGC CTGAGTGGTCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 97 1546 1546 QPVLTQPPSASGTPGQRVTISCSASSSNIGDNYFYWYQQLPGKAPTLLMY GSDQRSSGVPDRFSGSQSGTSASLAISGLRSEDEADYYCAAWDDSLSGPV FGGGTKLTVL 97 1547 1547 SASSSNIGDNYFY 97 1548 1548 TCTGCAAGCAGCTCCAACATCGGAGATAATTATTTCTAC 97 1549 1549 GSDQRSS 97 1550 1550 GGTAGTGATCAACGGTCCTCA 97 1551 1551 AAWDDSLSGPV 97 1552 1552 GCAGCTTGGGATGACAGCCTGAGTGGTCCGGTG 98 1553 1553 GAGGTGCAGCTGGTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGA GGTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACATTCAGTAACT TTGGGATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGG GTGGCAGCTATTTCATACGATGGAAGAAAAACATTCCAGGCAGACTC CGTGAAGGGCCGATTCATCATCTCCAGAGACAACTTGAAGAACACGT TGAATCTCCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTGTAT TACTGTGCGAAATCGTCTAGATTTTTGGACTGGTTATACAATATGGAC TTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 98 1554 1554 EVQLVESGGGVVQPGRSLRLSCAVSGFTFSNFGMHWVRQAPGKGLEWV AAISYDGRKTFQADSVKGRFIISRDNLKNTLNLQMNSLKTEDTAVYYCA KSSRFLDWLYNMDFWGQGTTVTVSS 98 1555 1555 FTFSNFGMH 98 1556 1556 TTCACATTCAGTAACTTTGGGATGCAC 98 1557 1557 AISYDGRKTFQADSVKG 98 1558 1558 GCTATTTCATACGATGGAAGAAAAACATTCCAGGCAGACTCCGTGAA GGGC 98 1559 1559 AKSSRFLDWLYNMDF 98 1560 1560 GCGAAATCGTCTAGATTTTTGGACTGGTTATACAATATGGACTTC 98 1561 1561 TCCTATGAGCTGACACAGCCACCCTCAGTGTCAGAGGCCCCAGGAAA GACGGCCACGATTACCTGTGGGGGAATCATCCTTGGGACTTCAAGTG TCCACTGGTTCCAGCAGAAGTCAGGCCAGGCCCCTGTCCTGGTCATCT ATTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT CCCATTCTGGGGACACGGCCACCCTGACCATCAGCAGGGTCGAAGTC GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAATAGTCATTC CCAGGGGGTCTTCGGCGGAGGCACCCAGCTGACCGTCCTC 98 1562 1562 SYELTQPPSVSEAPGKTATITCGGIILGTSSVHWFQQKSGQAPVLVIYYDS DRPSGIPERFSGSHSGDTATLTISRVEVGDEADYYCQVWDNSHSQGVFG GGTQLTVL 98 1563 1563 GGIILGTSSVH 98 1564 1564 GGGGGAATCATCCTTGGGACTTCAAGTGTCCAC 98 1565 1565 YDSDRPS 98 1566 1566 TATGATAGCGACCGGCCCTCA 98 1567 1567 QVWDNSHSQGV 98 1568 1568 CAGGTGTGGGATAATAGTCATTCCCAGGGGGTC 99 1569 1569 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCGCCTTCCGTGTCTA TGACATCCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG TGGCAGTTGCCTGGTCTGATGGACGTGATGAATTCTATGCAGACTCCG TGAAGGGCCGAATCACCATCTCCAGAGACAATTCAAAGAACACTGTA TATCTGCAGATGAGCAGCCTGAGAGTCGCGGATACGGCTGTGTATTA CTGTGCGAGAGATAGTGGGACCCTAACAGGGCTCCCTCATGATGCTT TTGATGTCTGGGGCCAGGGGACCACGGTCACCGTCTCCTCA 99 1570 1570 QVQLVESGGGVVQPGRSLRLSCAASGFAFRVYDIHWVRQAPGKGLEWV AVAWSDGRDEFYADSVKGRITISRDNSKNTVYLQMSSLRVADTAVYYC ARDSGTLTGLPHDAFDVWGQGTTVTVSS 99 1571 1571 FAFRVYDIH 99 1572 1572 TTCGCCTTCCGTGTCTATGACATCCAC 99 1573 1573 VAWSDGRDEFYADSVKG 99 1574 1574 GTTGCCTGGTCTGATGGACGTGATGAATTCTATGCAGACTCCGTGAAG GGC 99 1575 1575 ARDSGTLTGLPHDAFDV 99 1576 1576 GCGAGAGATAGTGGGACCCTAACAGGGCTCCCTCATGATGCTTTTGA TGTC 99 1577 1577 GACATCCAGTTGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTACCACCAG GTTGGCCTGGTATCAGCAGAAATTAGGGAAAGCCCCTAAGCTCCTGG TCTATAAGGCGTCAACTTTAGAAATTGGGGTCCCCTCAAGGTTCAGCG GCAGGGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG CCTGATGATTTTGCAACTTATTACTGCCATCACTACAATAGTTATTCG TGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 99 1578 1578 DIQLTQSPSTLSASVGDRVTITCRASQSITTRLAWYQQKLGKAPKLLVYK ASTLEIGVPSRFSGRGSGTEFTLTISSLQPDDFATYYCHHYNSYSWTFGQG TKVDIK 99 1579 1579 RASQSITTRLA 99 1580 1580 CGGGCCAGTCAGAGTATTACCACCAGGTTGGCC 99 1581 1581 KASTLEI 99 1582 1582 AAGGCGTCAACTTTAGAAATT 99 1583 1583 HHYNSYSWT 99 1584 1584 CATCACTACAATAGTTATTCGTGGACG 100 1585 1585 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCTGCCTCTGGATTCACTTTCACTGACTAT GCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGACTACAGTGGGT GGCACTTATATCATATAACGGACGTATACAATATTACGCAGACTCCGT GAAGGGCCGATTCACCATCTCCAGAGACGATTCCAAGAACACGCTGT ATCTGCAGATGAACAGCCTGAGAGCTGGGGACACGGCTGTCTATTAC TGTGCGAGAGATGGGGATCTTGTGGCTGTCCCAGCTGCTATCGGCTTC GACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 100 1586 1586 QVQLVESGGGVVQPGRSLRLSCAASGFTFTDYAMHWVRQAPGKGLQW VALISYNGRIQYYADSVKGRFTISRDDSKNTLYLQMNSLRAGDTAVYYC ARDGDLVAVPAAIGFDSWGQGTLVTVSS 100 1587 1587 FTFTDYAMH 100 1588 1588 TTCACTTTCACTGACTATGCTATGCAC 100 1589 1589 LISYNGRIQYYADSVKG 100 1590 1590 CTTATATCATATAACGGACGTATACAATATTACGCAGACTCCGTGAA GGGC 100 1591 1591 ARDGDLVAVPAAIGFDS 100 1592 1592 GCGAGAGATGGGGATCTTGTGGCTGTCCCAGCTGCTATCGGCTTCGA CTCC 100 1593 1593 GACATCCAGGTGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAC CTCCAACAACAAGAACTACTTAGCTTGGTACCAGCAGAAATCGAGAC AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG TCCCTGAGCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAG CAATATTCTAGTCCTCCGTACACTTTTGGCCAGGGGACCAAGGTGGA GATTAAA 100 1594 1594 DIQVTQSPDSLAVSLGERATINCKSSQSVLYTSNNKNYLAWYQQKSRQP PKLLIYWASTRESGVPERFSGSGSGTDFTLTISSLQAEDVAVYYCQQYSSP PYTFGQGTKVEIK 100 1595 1595 KSSQSVLYTSNNKNYLA 100 1596 1596 AAGTCCAGCCAGAGTGTTTTATACACCTCCAACAACAAGAACTACTT AGCT 100 1597 1597 WASTRES 100 1598 1598 TGGGCATCTACCCGGGAATCC 100 1599 1599 QQYSSPPYT 100 1600 1600 CAGCAATATTCTAGTCCTCCGTACACT 101 1601 1601 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAGGCCGGGGG GGTCCCTGAGACTCTCCTGCGCAGCGTCTGGATTCGCCTTCAGTAGCT ATAGTTTACACTGGGTCCGCCAGGCTCCAGGGAGGGGACTGGAGTGG GTCGCATCGATCAGTGCAGGTAGCAGTTTCACAGATTACGCGGCCTC AGTGAGGGGCCGATTCACTATCTCCAGAAACATCGCCAACTCACTGT ATCTGCAAATGAACAGGCTGAGAGCCGAGGACACGGCTGTCTATTAC TGTGCGAGAGTTATCGGAGACGGGACGATTCTTGGAGTGGTTTTTGAC TACTGGGGCCCGGGAACCCTGGTCACCGTCTCCTCA 101 1602 1602 EVQLVESGGGLVRPGGSLRLSCAASGFAFSSYSLHWVRQAPGRGLEWV ASISAGSSFTDYAASVRGRFTISRNIANSLYLQMNRLRAEDTAVYYCARV IGDGTILGVVFDYWGPGTLVTVSS 101 1603 1603 FAFSSYSLH 101 1604 1604 TTCGCCTTCAGTAGCTATAGTTTACAC 101 1605 1605 SISAGSSFTDYAASVRG 101 1606 1606 TCGATCAGTGCAGGTAGCAGTTTCACAGATTACGCGGCCTCAGTGAG GGGC 101 1607 1607 ARVIGDGTILGVVFDY 101 1608 1608 GCGAGAGTTATCGGAGACGGGACGATTCTTGGAGTGGTTTTTGACTAC 101 1609 1609 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA GAGGGTCACCATCTCCTGCACTGGGGGCAGGTCCAACATCGGGGCCG GTTATGATGTACACTGGTACCAGCAACTTCCAGGGACAGCCCCCAAA CTCCTCATCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGACCGA TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG CTCCTGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC AGCCTGAGTGTGATTTTCGGCGGAGGGACCAAGCTCACCGTCCTA 101 1610 1610 QSVLTQPPSVSGAPGQRVTISCTGGRSNIGAGYDVHWYQQLPGTAPKLLI YGNINRPSGVPDRFSGSKSGTSASLAITGLLAEDEADYYCQSYDSSLSVIF GGGTKLTVL 101 1611 1611 TGGRSNIGAGYDVH 101 1612 1612 ACTGGGGGCAGGTCCAACATCGGGGCCGGTTATGATGTACAC 101 1613 1613 GNINRPS 101 1614 1614 GGTAACATCAATCGGCCCTCA 101 1615 1615 QSYDSSLSVI 101 1616 1616 CAGTCCTATGACAGCAGCCTGAGTGTGATT 102 1617 1617 CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACGTCTTTAGTAGTT ACTGGGTCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG ATGGGGATCATCTATCCTCATGACTCTGATACCAGATACAGCCCGGCC TTCCAAGGCCAGGTCACCATTTCAGCCGATAAGTCCATCAACACCGC CTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATT ACTGCACCATTATACTAATACCAGCTCCTATACGGGCCCCTGATGGTT TTGATATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 102 1618 1618 QVQLVQSGAEVKKPGESLKISCKGSGYVFSSYWVAWVRQMPGKGLEW MGIIYPHDSDTRYSPAFQGQVTISADKSINTAYLQWSSLKASDTAMYYCT IILIPAPIRAPDGFDIWGQGTTVTVSS 102 1619 1619 YVFSSYWVA 102 1620 1620 TACGTCTTTAGTAGTTACTGGGTCGCC 102 1621 1621 IIYPHDSDTRYSPAFQG 102 1622 1622 ATCATCTATCCTCATGACTCTGATACCAGATACAGCCCGGCCTTCCAA GGC 102 1623 1623 TIILIPAPIRAPDGFDI 102 1624 1624 ACCATTATACTAATACCAGCTCCTATACGGGCCCCTGATGGTTTTGAT ATC 102 1625 1625 AATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAG ACGGTAACCATCTCCTGCACCGGCAGCGGTGGCACCATTGCCAGCAA CTATGTGCAGTGGTACCAGCAGCGCCCGGGCAGTGTCCCCACCACTG TGATCTATGAGAATAACGAAAGACCCTCTGGGGTCCCTGATCGGTTCT CTGGCTCCATCGACAGGTCCTCCAACTCTGCCTCCCTCACCATCTCTG GACTGAAGACTGAGGACGAGGCTGACTACTACTGTCAGTCTTATGAT AGCAGCTATCATGTGGTATTCGGCGGAGGGACCAAGGTCACCGTCCTA 102 1626 1626 NFMLTQPHSVSESPGKTVTISCTGSGGTIASNYVQWYQQRPGSVPTTVIY ENNERPSGVPDRFSGSIDRSSNSASLTISGLKTEDEADYYCQSYDSSYHVV FGGGTKVTVL 102 1627 1627 TGSGGTIASNYVQ 102 1628 1628 ACCGGCAGCGGTGGCACCATTGCCAGCAACTATGTGCAG 102 1629 1629 ENNERPS 102 1630 1630 GAGAATAACGAAAGACCCTCT 102 1631 1631 QSYDSSYHVV 102 1632 1632 CAGTCTTATGATAGCAGCTATCATGTGGTA 103 1633 1633 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGACACGTTCAGCAGCT ATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGG ATGGGAGGGGTCCTCCCTATGTTAGGGACAGCAAACTACGCACAGAG GTTCCGGGGCAGAGTCACACTTACCGCGGACGGATCCACGAACACAG CCTACATGGAGATGAGCAGCCTGAGACTTGACGACACGGCCGTGTAT TACTGTGCGAGAGTGGCCGGTCTGGGAAATAGCTACGGTCGATACCC TGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 103 1634 1634 QVQLVQSGAEVKKPGSSVKVSCKASGDTFSSYAISWVRQAPGQGLEWM GGVLPMLGTANYAQRFRGRVTLTADGSTNTAYMEMSSLRLDDTAVYY CARVAGLGNSYGRYPDLWGQGTLVTVSS 103 1635 1635 DTFSSYAIS 103 1636 1636 GACACGTTCAGCAGCTATGCTATCAGC 103 1637 1637 GVLPMLGTANYAQRFRG 103 1638 1638 GGGGTCCTCCCTATGTTAGGGACAGCAAACTACGCACAGAGGTTCCG GGGC 103 1639 1639 ARVAGLGNSYGRYPDL 103 1640 1640 GCGAGAGTGGCCGGTCTGGGAAATAGCTACGGTCGATACCCTGACCTC 103 1641 1641 GATATTGTGATGACCCAGTCTCCATCTTCTCTGTCTGCATCTGTTGGA GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTC GTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTGAGCTCCTGA TCTATGCTGCATCCAGTTTGCACAGTGGGGTCCCATCGAGGTTCCGGG GCAGTGGATCTGGGACAGACTTCACTCTCACTATCAGCAGCGTGCAG CCTGAAGATTTTGCAACTTACTATTGTCAACAGGCAAACAGTTTCCCG TACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 103 1642 1642 DIVMTQSPSSLSASVGDRVTITCRASQGISSSLAWYQQKPGKAPELLIYAA SSLHSGVPSRFRGSGSGTDFTLTISSVQPEDFATYYCQQANSFPYTFGQGT KLEIK 103 1643 1643 RASQGISSSLA 103 1644 1644 CGGGCGAGTCAGGGTATTAGCAGCTCGTTAGCC 103 1645 1645 AASSLHS 103 1646 1646 GCTGCATCCAGTTTGCACAGT 103 1647 1647 QQANSFPYT 103 1648 1648 CAACAGGCAAACAGTTTCCCGTACACT 104 1649 1649 CAGGTCCAGCTTGTACAGTCTGGAGCAGAGGTGAAAAAGCCGGGGG AGTCTCTGAAGATCTCCTGTAAGGGTGCAGGATTCGGCTCTACCAACT CCTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG ATGGGGGTCATCTTTCCAGGTGACTCTGATACCAAATACAGCCCGAC CTTCCAAGGCCAGGTCACCATCTCAGTCGACAAGTCCATCAACACCG CCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATCTAT TACTGTGCGAGAATGCTGGCTTCTGTTGGTTTGTCCAACTTTGACGCG TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 104 1650 1650 QVQLVQSGAEVKKPGESLKISCKGAGFGSTNSWIGWVRQMPGKGLEW MGVIFPGDSDTKYSPTFQGQVTISVDKSINTAYLQWSSLKASDTAIYYCA RMLASVGLSNFDAWGQGTLVTVSS 104 1651 1651 FGSTNSWIG 104 1652 1652 TTCGGCTCTACCAACTCCTGGATCGGC 104 1653 1653 VIFPGDSDTKYSPTFQG 104 1654 1654 GTCATCTTTCCAGGTGACTCTGATACCAAATACAGCCCGACCTTCCAA GGC 104 1655 1655 ARMLASVGLSNFDA 104 1656 1656 GCGAGAATGCTGGCTTCTGTTGGTTTGTCCAACTTTGACGCG 104 1657 1657 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCACTGGCCCCAGGAAA GACGGCCACGATTACCTGTGGGGGAAACAACATTGGAGGTAAAAGTG TGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCATC GATTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGG CTCCAACTCTGGGAACACGGCCACCCTGACCATCAACAGGGTCGAAG CCGGGGATGAGGCCGACTACTACTGTCAGGTGTGGGATAGTATTAGT GATCATGTGTTATTCGGTGGAGGGACCAAGCTGACCGTCCTA 104 1658 1658 QPVLTQPPSVSLAPGKTATITCGGNNIGGKSVHWYQQKPGQAPVLVIDY DSDRPSGIPERFSGSNSGNTATLTINRVEAGDEADYYCQVWDSISDHVLF GGGTKLTVL 104 1659 1659 GGNNIGGKSVH 104 1660 1660 GGGGGAAACAACATTGGAGGTAAAAGTGTGCAC 104 1661 1661 YDSDRPS 104 1662 1662 TATGATAGCGACCGGCCCTCA 104 1663 1663 QVWDSISDHVL 104 1664 1664 CAGGTGTGGGATAGTATTAGTGATCATGTGTTA 105 1665 1665 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTAAGCCTGGGGG GTCCCTTAGACTCTCTTGTGCAGCCTCTGGATTCACTTTCAGTAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGTGTTAAAAGCAAATCTAAAGGTGGGACAACACACTACGCT GAAGCCGTGAAGGGCAGATTCACCATTTCAAGAGATGATTCAAAAAA CACGCTGTACCTCCAAATGCAGAGCCTGAAAACCGAGGACACAGCCG TCTATTACTGTACCTCCCACGCGTATAATAGTGACTGGTTCGTGACGA CTGACTACTACTACTACATGGACGTCTGGGGCAAAGGGACCACGGTC ACCGTCTCCTCA 105 1666 1666 EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEW VGRVKSKSKGGTTHYAEAVKGRFTISRDDSKNTLYLQMQSLKTEDTAV YYCTSHAYNSDWFVTTDYYYYMDVWGKGTTVTVSS 105 1667 1667 FTFSNAWMS 105 1668 1668 TTCACTTTCAGTAACGCCTGGATGAGC 105 1669 1669 RVKSKSKGGTTHYAEAVKG 105 1670 1670 CGTGTTAAAAGCAAATCTAAAGGTGGGACAACACACTACGCTGAAGC CGTGAAGGGC 105 1671 1671 TSHAYNSDWFVTTDYYYYMDV 105 1672 1672 ACCTCCCACGCGTATAATAGTGACTGGTTCGTGACGACTGACTACTAC TACTACATGGACGTC 105 1673 1673 GATATTGTGCTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGA GACAGAGTCACCTTCACTTGCCGGGCAAGTCAGAGCATTAGCAACTA TTTGAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGA TCTATGGTGCTTCCAATTTGCTAAGTGGGGTCCCATCAAGGTTCATTG GCAGCGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAA CCTGAAGATTTTGCAACTTACTACTGTCAACAGTGTTACAGTGCCCCG ATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 105 1674 1674 DIVLTQSPSSLSASVGDRVTFTCRASQSISNYLNWYQQKPGKAPKVLIYG ASNLLSGVPSRFIGSGSGTDFTLTINSLQPEDFATYYCQQCYSAPITFGQG TRLEIK 105 1675 1675 RASQSISNYLN 105 1676 1676 CGGGCAAGTCAGAGCATTAGCAACTATTTGAAT 105 1677 1677 GASNLLS 105 1678 1678 GGTGCTTCCAATTTGCTAAGT 105 1679 1679 QQCYSAPIT 105 1680 1680 CAACAGTGTTACAGTGCCCCGATCACC 106 1681 1681 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAAGGTCTCCTGCACGGCCTCTGGAGGCAGCTTCAGCACCA ATAGTATTGCCTGGCTGAGGCAGACCCCTAGAGAAGGGCTGGAGTGG ATGGGAGGAATCATCCCTGTCTTTGGTGCAGCAAAATACGCACAGAA GTTCCAGGGCAGAGTCACGATTAGCGCGGACGCATCCACGACCACAG CCTACTTGGAGCTGCACAACCTGAGATCTGAGGACACTGCCGTCTATT ACTGCGCGAGAGGAATTTCCCCCAGGACAAACAGTGACTGGAACCAC AACTACTTCTACTACTACATGGACGTCTGGGGCAAAGGGACCACGGT CACCGTCTCCTCA 106 1682 1682 QVQLVQSGAEVKKPGSSVKVSCTASGGSFSTNSIAWLRQTPREGLEWMG GIIPVFGAAKYAQKFQGRVTISADASTTTAYLELHNLRSEDTAVYYCARG ISPRTNSDWNHNYFYYYMDVWGKGTTVTVSS 106 1683 1683 GSFSTNSIA 106 1684 1684 GGCAGCTTCAGCACCAATAGTATTGCC 106 1685 1685 GIIPVFGAAKYAQKFQG 106 1686 1686 GGAATCATCCCTGTCTTTGGTGCAGCAAAATACGCACAGAAGTTCCA GGGC 106 1687 1687 ARGISPRTNSDWNHNYFYYYMDV 106 1688 1688 GCGAGAGGAATTTCCCCCAGGACAAACAGTGACTGGAACCACAACTA CTTCTACTACTACATGGACGTC 106 1689 1689 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG GAGAGAGCCACCCTCTCCTGCCGGGCCAGTCAGAGTATTTTCACCATC TACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCT CATCTATAGTGCATCCAACAGGGCCACTGGCATCCCAGACAGGTTCA GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTG GAGCCTGAAGATTTTGCAGTCTATTACTGCCACCACTATGGTACCTCA CCTCACACTTTTGGCCAGGGGACACGACTGGAGATTAAA 106 1690 1690 ETTLTQSPGTLSLSPGERATLSCRASQSIFTIYLAWYQQKPGQAPRLLIYS ASNRATGIPDRFSGSGSGTDFTLTISSLEPEDFAVYYCHHYGTSPHTFGQG TRLEIK 106 1691 1691 RASQSIFTIYLA 106 1692 1692 CGGGCCAGTCAGAGTATTTTCACCATCTACTTAGCC 106 1693 1693 SASNRAT 106 1694 1694 AGTGCATCCAACAGGGCCACT 106 1695 1695 HHYGTSPHT 106 1696 1696 CACCACTATGGTACCTCACCTCACACT 107 1697 1697 GAGGTGCAGCTGTTGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGA GACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACTCGCCAATCC TGACGTGGCTGTGGCCTGGATCCGTCAGCCCCCCGGGAAGGCCCTGG AGTGGCTTGCACACATTTTTTCGGGCGACGAAACATCCTACACCACAT CTCTGCAGAACAGACTCACCATCTCCAAGGACACCTCCAAAAGCCAG GTTGTCCTTATCATGACCAAGATGGACCCTCGAGACACCGGCACATA TTTCTGTGCACGGGTGTTGACTACCTGGCACGGACCGGACTACTGGG GCCAGGGGACCACGGTCACCGTCTCCTCA 107 1698 1698 EVQLLESGPVLVKPTETLTLTCTVSGFSLANPDVAVAWIRQPPGKALEW LAHIFSGDETSYTTSLQNRLTISKDTSKSQVVLIMTKMDPRDTGTYFCAR VLTTWHGPDYWGQGTTVTVSS 107 1699 1699 FSLANPDVAVA 107 1700 1700 TTCTCACTCGCCAATCCTGACGTGGCTGTGGCC 107 1701 1701 HIFSGDETSYTTSLQN 107 1702 1702 CACATTTTTTCGGGCGACGAAACATCCTACACCACATCTCTGCAGAAC 107 1703 1703 ARVLTTWHGPDY 107 1704 1704 GCACGGGTGTTGACTACCTGGCACGGACCGGACTAC 107 1705 1705 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA CAGCCGGCCTCCATCTCCTGCAGGTCTGATCAAAGCCTCGTATATCAT AATGGAAACACCTACGTGAGTTGGTTTCATCAGAGGCCAGGCCAATC TCCAAGGCGCCTAATTTATAAGGTTTCTATCCGGGACTCTGGGGTCCC AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCGCACTGAAAA TCAGCAGGGTGGAGGCTGAGGATCTTGGGGTTTATTACTGCATGCAA GGTTCACACTGGCCGCACACTTTTGGCCAGGGGACCAAAGTGGATAT CAAA 107 1706 1706 ETTLTQSPLSLPVTLGQPASISCRSDQSLVYHNGNTYVSWFHQRPGQSPR RLIYKVSIRDSGVPDRFSGSGSGTDFALKISRVEAEDLGVYYCMQGSHWP HTFGQGTKVDIK 107 1707 1707 RSDQSLVYHNGNTYVS 107 1708 1708 AGGTCTGATCAAAGCCTCGTATATCATAATGGAAACACCTACGTGAGT 107 1709 1709 KVSIRDS 107 1710 1710 AAGGTTTCTATCCGGGACTCT 107 1711 1711 MQGSHWPHT 107 1712 1712 ATGCAAGGTTCACACTGGCCGCACACT 108 1713 1713 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCGTTTAGTACCTCT TGGATGAGTTGGGTCCGCCAGGCTCCAGGGAAAGGTCTGGAGTGGCT GGCCAACATAAAGGAAGATGGAAGTAAGAAAATCTATGTGGACTCTG TGAAGGGCCGCTTCTCCATATCCAGGGACAACGCCAAGAACTCACTG TATCTGCAAATGACCAGCCTAAGAGCCGAGGACACGGCCGTGTATTA TTGTGCGAGAGATGTGTGGGGGTGGGAGCTAGTCGGATGGTTGGACC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 108 1714 1714 EVQLVESGGGLVQPGGSLRLSCAASGFSFSTSWMSWVRQAPGKGLEWL ANIKEDGSKKIYVDSVKGRFSISRDNAKNSLYLQMTSLRAEDTAVYYCA RDVWGWELVGWLDPWGQGTLVTVSS 108 1715 1715 FSFSTSWMS 108 1716 1716 TTCTCGTTTAGTACCTCTTGGATGAGT 108 1717 1717 NIKEDGSKKIYVDSVKG 108 1718 1718 AACATAAAGGAAGATGGAAGTAAGAAAATCTATGTGGACTCTGTGAA GGGC 108 1719 1719 ARDVWGWELVGWLDP 108 1720 1720 GCGAGAGATGTGTGGGGGTGGGAGCTAGTCGGATGGTTGGACCCC 108 1721 1721 TCCTATGAGCTGACACAGCCACCCTCGGTATCAGTGGCCCCAGGAAA GACGGCCAGCATTACCTGTGGGGGAAGCAACATTGGAAGTAGAAGTG TGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTC TATGAGGATCACGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGG CTCCAACTCTGGGAATACGGCCACCCTGACCATCAGCAGGGTCGAAG CCGGGGACGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGA GATCATGTGGTATTCGGCGGCGGGACCAAGGTCACCGTCCTA 108 1722 1722 SYELTQPPSVSVAPGKTASITCGGSNIGSRSVHWYQQKPGQAPVLVVYE DHDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSRDHVV FGGGTKVTVL 108 1723 1723 GGSNIGSRSVH 108 1724 1724 GGGGGAAGCAACATTGGAAGTAGAAGTGTGCAC 108 1725 1725 EDHDRPS 108 1726 1726 GAGGATCACGACCGGCCCTCA 108 1727 1727 QVWDSSRDHVV 108 1728 1728 CAGGTGTGGGATAGTAGTAGAGATCATGTGGTA 109 1729 1729 GAGGTGCAGCTGGTGGAGTCTGGTCCTGCGCTGGTGAAACCCACACA GACCCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCAGTAG AAGAATGTGTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG AGTGGCTTGCACGCATTGATTGGGATGATGATAAATCCTACAGCACA TCTCTGAAGACCAGGCTCACCATCGCCAAGGACACCTCCAAAAACCA GGTCGTCCTTACAATGACCAACATGGGCCCCGCGGACACAGCCACGT ATTACTGTGCACGGACTCCTATATATGATAGTAGTGGTTATTACCTCT ACTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 109 1730 1730 EVQLVESGPALVKPTQTLTLTCTFSGFSLSSRRMCVSWIRQPPGKALEWL ARIDWDDDKSYSTSLKTRLTIAKDTSKNQVVLTMTNMGPADTATYYCA RTPIYDSSGYYLYYFDSWGQGTLVTVSS 109 1731 1731 FSLSSRRMCVS 109 1732 1732 TTCTCACTCAGCAGTAGAAGAATGTGTGTGAGT 109 1733 1733 RIDWDDDKSYSTSLKT 109 1734 1734 CGCATTGATTGGGATGATGATAAATCCTACAGCACATCTCTGAAGACC 109 1735 1735 ARTPIYDSSGYYLYYFDS 109 1736 1736 GCACGGACTCCTATATATGATAGTAGTGGTTATTACCTCTACTACTTT GACTCC 109 1737 1737 GAAACGACACTCACGCAGTCTCCATCCTCCCTGTCTGCATCTGTCGGA GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAA CCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCT GTGACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 109 1738 1738 ETTLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAA SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPVTFGQGT KVEIK 109 1739 1739 RASQSISSYLN 109 1740 1740 CGGGCAAGTCAGAGCATTAGCAGCTATTTAAAT 109 1741 1741 AASSLQS 109 1742 1742 GCTGCATCCAGTTTGCAAAGT 109 1743 1743 QQSYSTPVT 109 1744 1744 CAACAGAGTTACAGTACCCCTGTGACT 110 1745 1745 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTA TGCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGCCTCCAGTGGG TGTCACTTATATCATATAATGGACGTAAAAAATATTACGCAGACTCCG TGAAGGGCCGATTCACCATCTCCAGAGACGATTCCAAGAACACGCTG TATCTGCAAATGAACCCCCTGAGACCTGACGACACGGCTGTCTATTAC TGTGCGAGAGATGGGGATATTGTAGCTGTTCCAGCTGCTATCGGGTTG GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 110 1746 1746 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSDYAMHWVRQAPGKGLQW VSLISYNGRKKYYADSVKGRFTISRDDSKNTLYLQMNPLRPDDTAVYYC ARDGDIVAVPAAIGLDYWGQGTLVTVSS 110 1747 1747 FTFSDYAMH 110 1748 1748 TTCACCTTCAGTGACTATGCTATGCAC 110 1749 1749 LISYNGRKKYYADSVKG 110 1750 1750 CTTATATCATATAATGGACGTAAAAAATATTACGCAGACTCCGTGAA GGGC 110 1751 1751 ARDGDIVAVPAAIGLDY 110 1752 1752 GCGAGAGATGGGGATATTGTAGCTGTTCCAGCTGCTATCGGGTTGGA CTAC 110 1753 1753 GATATTGTGCTGACCCAGTCTCCAGAGTCCCTGGCTGTGTCTCTGGGC GAGAGGGCCACCATCAACTGCAACTCCAGCCAGAGTGTTTTATACAC CTCCAACAACAAGAACTACTTAGCTTGGTACCAGCAGAAATCAGGAC AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG TCCCTGAGCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAG CAATATTCTAGTCCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAG ATCAAA 110 1754 1754 DIVLTQSPESLAVSLGERATINCNSSQSVLYTSNNKNYLAWYQQKSGQPP KLLIYWASTRESGVPERFSGSGSGTDFTLTISSLQAEDVAVYYCQQYSSPP YTFGQGTKLEIK 110 1755 1755 NSSQSVLYTSNNKNYLA 110 1756 1756 AACTCCAGCCAGAGTGTTTTATACACCTCCAACAACAAGAACTACTT AGCT 110 1757 1757 WASTRES 110 1758 1758 TGGGCATCTACCCGGGAATCC 110 1759 1759 QQYSSPPYT 110 1760 1760 CAGCAATATTCTAGTCCTCCGTACACT 111 1761 1761 CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACTAGTGAAGCCTTCAGA GACCCTGTCCCTCACTTGCAGTGTCTCTGGTGGCTCCATCAAAAGAGG TGCTTACTTCTGGACCTGGATCCGCCAGCGGCCAGGGAAGGGCCTGG AGTGGATTGGGTCCATGCATGACAGCGGCGACTACTACAACCCGTCC CTCAAGACACGCGTTACCATTTTGGGAGACACGACTAAGAACCACTT CACCCTGAAGTTGACCTCCGTGACTGTCGCGGACACGGCCTTATATTA CTGTGCGAGGGGGCGCGGATACAGCTATGGCTGGCGTTTCTTTGACA ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 111 1762 1762 QVQLQESGPGLVKPSETLSLTCSVSGGSIKRGAYFWTWIRQRPGKGLEWI GSMHDSGDYYNPSLKTRVTILGDTTKNHFTLKLTSVTVADTALYYCARG RGYSYGWRFFDNWGQGTLVTVSS 111 1763 1763 GSIKRGAYFWT 111 1764 1764 GGCTCCATCAAAAGAGGTGCTTACTTCTGGACC 111 1765 1765 SMHDSGDYYNPSLKT 111 1766 1766 TCCATGCATGACAGCGGCGACTACTACAACCCGTCCCTCAAGACA 111 1767 1767 ARGRGYSYGWRFFDN 111 1768 1768 GCGAGGGGGCGCGGATACAGCTATGGCTGGCGTTTCTTTGACAAC 111 1769 1769 AATTTTATGCTGACTCAGCCCCCCTCGGTGTCAGTGTCCCCAGGACAC TCGACCAGGATCACCTGCTCTGGAGATGCTTTGCCAAAGCAATATGCT TATTGGTATCAGCAGAAGCCAGGCCAGGCCCCTGTCCTGATAATGTC CAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCACTGGCT CCAGCTCAGGGACTACAGTCACTTTGACCATCAGTGGAGTCCAGGCA GAGGACGAGGCCGACTATTACTGTCAATCAGGAGACACCAGTGGAAG TTATGTCGTCTTCGGCGGAGGGACCAAGGTCACCGTCCTA 111 1770 1770 NFMLTQPPSVSVSPGHSTRITCSGDALPKQYAYWYQQKPGQAPVLIMSK DSERPSGIPERFTGSSSGTTVTLTISGVQAEDEADYYCQSGDTSGSYVVFG GGTKVTVL 111 1771 1771 SGDALPKQYAY 111 1772 1772 TCTGGAGATGCTTTGCCAAAGCAATATGCTTAT 111 1773 1773 KDSERPS 111 1774 1774 AAAGACAGTGAGAGGCCCTCA 111 1775 1775 QSGDTSGSYVV 111 1776 1776 CAATCAGGAGACACCAGTGGAAGTTATGTCGTC 112 1777 1777 GAGGTGCAGCTGTTGGAGTCCGGGCCAGAGTTGAAGAAGCCTGGGTC CTCGGTGAAGGTGTCTTGCAAGGCCTCTGCAGACACTTTCAATGGTCA CTCAATTGCTTGGGTGCGGCAGGCCCCTGGACAAGGGCTTGAGTGGG TGGGAGGATTCATCCCCATTTTTGGGAAAGCATACTACGCACAGAAC TTCCAGGGCACAGTCACGATTTCCGCGGATTCTTCCACGAGAACAGTC TACATGGATCTGTTCAACCTGAGATCTGAGGACACGGCCGTCTATTAC TGTGCGAGATCAAGGAAAAATGTTATCGGGGACACCAGTGCCTGGGA ACATATGTACTTCTACATGGACGTCTGGGGCACCGGGACCACGGTCA CCGTCTCCTCA 112 1778 1778 EVQLLESGPELKKPGSSVKVSCKASADTFNGHSIAWVRQAPGQGLEWV GGFIPIFGKAYYAQNFQGTVTISADSSTRTVYMDLFNLRSEDTAVYYCAR SRKNVIGDTSAWEHMYFYMDVWGTGTTVTVSS 112 1779 1779 DTFNGHSIA 112 1780 1780 GACACTTTCAATGGTCACTCAATTGCT 112 1781 1781 GFIPIFGKAYYAQNFQG 112 1782 1782 GGATTCATCCCCATTTTTGGGAAAGCATACTACGCACAGAACTTCCAG GGC 112 1783 1783 ARSRKNVIGDTSAWEHMYFYMDV 112 1784 1784 GCGAGATCAAGGAAAAATGTTATCGGGGACACCAGTGCCTGGGAAC ATATGTACTTCTACATGGACGTC 112 1785 1785 GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG GAAAGAGTCACTCTCTCCTGCAGGGCCAGTGAGAGTATTAATAAGAA TACCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGC TCCTCATTTATGGAGCATCCAGCAGGGCCACTGGCATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTGGAGCCTGAAGATTCTGCTGTGTATTACTGTCAGCAATATGGTAG GTCAATGACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 112 1786 1786 EIVLTQSPGTLSLSPGERVTLSCRASESINKNTYLAWYQQKPGQAPRLLIY GASSRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYGRSMTFGG GTKVEIK 112 1787 1787 RASESINKNTYLA 112 1788 1788 AGGGCCAGTGAGAGTATTAATAAGAATACCTACTTAGCC 112 1789 1789 GASSRAT 112 1790 1790 GGAGCATCCAGCAGGGCCACT 112 1791 1791 QQYGRSMT 112 1792 1792 CAGCAATATGGTAGGTCAATGACT 113 1793 1793 CAGGTCCAGCTTGTACAGTCTGGGACTGAGGTGAAGAAGCCTGGGTC CTCGGTGAATGTCTCCTGCAAGGCTGTTGGAGGCAAGTTCACCAGTTA TAATATTAACTGGGTGCGACAGGCCCCTGGACAAGGCCTTGAGTGGA TGGGAAGGATCATCCCAACCCTTGGTATAACATACTTCGCACAGAAG TTCCAGGGCAGACTCACGATTAACGCGGACAGATCCACGAGCACCGC CTACATGGATCTGAGCAGCCTGAGATCTGACGATACGGCCGTTTATTA TTGTGCGAGATCCAATCCCGTTGCTCGCGATTTTTGGAGTGGATATTC TGACGACTCCTCCTATGCTATGGACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 113 1794 1794 QVQLVQSGTEVKKPGSSVNVSCKAVGGKFTSYNINWVRQAPGQGLEW MGRIIPTLGITYFAQKFQGRLTINADRSTSTAYMDLSSLRSDDTAVYYCA RSNPVARDFWSGYSDDSSYAMDVWGQGTTVTVSS 113 1795 1795 GKFTSYNIN 113 1796 1796 GGCAAGTTCACCAGTTATAATATTAAC 113 1797 1797 RIIPTLGITYFAQKFQG 113 1798 1798 AGGATCATCCCAACCCTTGGTATAACATACTTCGCACAGAAGTTCCA GGGC 113 1799 1799 ARSNPVARDFWSGYSDDSSYAMDV 113 1800 1800 GCGAGATCCAATCCCGTTGCTCGCGATTTTTGGAGTGGATATTCTGAC GACTCCTCCTATGCTATGGACGTC 113 1801 1801 GAAACGACACTCACGCAGTCTCCAGGAACCCTGTCTTTGTCTCCAGG GGACAGAGTCAGCCTCTCCTGCAGGGCCAGTCAGACTGTTGACAAGA ACTACGTAGCCTGGTACCAGCAGAAGCCTGGCCAGGCTCCCAGGCTC CTCATCTATGGTGCATCCAAGAGGGCCGCTGACATCCCAGACAGGTT CAGTGGCAGTGGCTCTGGGGCAGACTTCACTCTCACCATCAGCAGAC TGGAGCCTGAAGATTTTGCTGTGTATCACTGTCAGCAGTATGGAGCTT CAGCGTTCAGTTTCGGCGGCGGGACCAAGCTGGAGATCAAA 113 1802 1802 ETTLTQSPGTLSLSPGDRVSLSCRASQTVDKNYVAWYQQKPGQAPRLLI YGASKRAADIPDRFSGSGSGADFTLTISRLEPEDFAVYHCQQYGASAFSF GGGTKLEIK 113 1803 1803 RASQTVDKNYVA 113 1804 1804 AGGGCCAGTCAGACTGTTGACAAGAACTACGTAGCC 113 1805 1805 GASKRAA 113 1806 1806 GGTGCATCCAAGAGGGCCGCT 113 1807 1807 QQYGASAFS 113 1808 1808 CAGCAGTATGGAGCTTCAGCGTTCAGT 114 1809 1809 CAGGTGCAGCTGGTGCAATCTGGGGGAGGCTTGGTAAAGCCGGGGGG GTCCCTTAGACTCTCATGTGCAGCCTCTGGATTCGCTTTCAGTAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGC TTGGCCGTATTAAAAGCGAAACTGACGGTGGGACAACAGACTACGCT GCACCCGTGAAAGGCAGATTCAGCATCTCAAGAGATGATTCCAGAAA CACGCTGTATCTGCAAATGAACAGCCTGGAAAGCGAGGACACAGCCG TTTATTACTGTACCACAGGCCCACCCTATAAGTATTTTGATAGTACTG GTTATTCGGTCGTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 114 1810 1810 QVQLVQSGGGLVKPGGSLRLSCAASGFAFSNAWMSWVRQAPGKGLEW LGRIKSETDGGTTDYAAPVKGRFSISRDDSRNTLYLQMNSLESEDTAVYY CTTGPPYKYFDSTGYSVVDYWGQGTLVTVSS 114 1811 1811 FAFSNAWMS 114 1812 1812 TTCGCTTTCAGTAACGCCTGGATGAGC 114 1813 1813 RIKSETDGGTTDYAAPVKG 114 1814 1814 CGTATTAAAAGCGAAACTGACGGTGGGACAACAGACTACGCTGCACC CGTGAAAGGC 114 1815 1815 TTGPPYKYFDSTGYSVVDY 114 1816 1816 ACCACAGGCCCACCCTATAAGTATTTTGATAGTACTGGTTATTCGGTC GTTGACTAC 114 1817 1817 TCCTATGAGCTGACACAGCCACCCTCAGCGTCTGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAATATCGGAAGTA ATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAGACTC CTCATCTATAGTACTAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC TCTGGCTCCCAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC CGGTCCGACGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG GATGAGTGGTCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 114 1818 1818 SYELTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPRLLIYS TNQRPSGVPDRFSGSQSGTSASLAISGLRSDDEADYYCAAWDDRMSGPV FGGGTKLTVL 114 1819 1819 SGSSSNIGSNYVY 114 1820 1820 TCTGGAAGCAGCTCCAATATCGGAAGTAATTATGTATAC 114 1821 1821 STNQRPS 114 1822 1822 AGTACTAATCAGCGGCCCTCA 114 1823 1823 AAWDDRMSGPV 114 1824 1824 GCAGCATGGGATGACAGGATGAGTGGTCCGGTG 115 1825 1825 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGG GTCCCTAAGACTCTCCTGTGCAGCCTCTGGACTCACCTTTAGCTCTTA TGCCATGTCCTGGGTCCGCCAGGCTCCAGGGAAGGAACTGGAGTGGG TCTCATCTATTAGTGAAAGTGGTGTTGATACATACTACGCAGACTCCG TGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAAAGCACGCTG TATCTGCAAATGAGCAGCCTGGGAGGCGACGACACGGCCGTATATTA TTGCGCGAAGGCATACTGTAGTAATAAGGCCTGCCACGGGGGCTACT TTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 115 1826 1826 QVQLVQSGGGLVQPGGSLRLSCAASGLTFSSYAMSWVRQAPGKELEWV SSISESGVDTYYADSVKGRFTVSRDNSKSTLYLQMSSLGGDDTAVYYCA KAYCSNKACHGGYFDYWGQGTLVTVSS 115 1827 1827 LTFSSYAMS 115 1828 1828 CTCACCTTTAGCTCTTATGCCATGTCC 115 1829 1829 SISESGVDTYYADSVKG 115 1830 1830 TCTATTAGTGAAAGTGGTGTTGATACATACTACGCAGACTCCGTGAA GGGC 115 1831 1831 AKAYCSNKACHGGYFDY 115 1832 1832 GCGAAGGCATACTGTAGTAATAAGGCCTGCCACGGGGGCTACTTTGA CTAC 115 1833 1833 GAAACGACACTCACGCAGTCTCCAGACACCCTGTCCTTGTCTCCAGG GGAAAGGGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGGAACT ACTTAGCCTGGTACCGGCAGAAACCTGGCCAGGCTCCCAGGCTCCTC ATCTATGATGCATCCAACCTGGCCACTGGCATCCCAGCCAGGTTCAGT GGCAGCGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGA GCCTGAAGATTTTGCAGTTTATTACTGTCACCAGCGTAGCGACTGGCC GCTCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 115 1834 1834 ETTLTQSPDTLSLSPGERATLSCRASQSVRNYLAWYRQKPGQAPRLLIYD ASNLATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQRSDWPLTFGPG TKVEIK 115 1835 1835 RASQSVRNYLA 115 1836 1836 AGGGCCAGTCAGAGTGTTAGGAACTACTTAGCC 115 1837 1837 DASNLAT 115 1838 1838 GATGCATCCAACCTGGCCACT 115 1839 1839 HQRSDWPLT 115 1840 1840 CACCAGCGTAGCGACTGGCCGCTCACT 116 1841 1841 GAGGTGCAGCTGGTGGAGTCGGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGGAGCTA TTGGATGACCTGGGTCCGCCAGGCTCCAGGGAAAGGGCTGGAGTGGG TGGCCAGCATAAACGATGAGGGGAATACTAAATACTATGTGGACTCT CTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT TTATCTCCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTTTATT ACTGTGCGAGGGAGTCCGGTCTGCCCCGGGGTGCCTTTCAAATCTGG GGCCCAGGGACAATGGTCACCGTCTCTTCA 116 1842 1842 EVQLVESGGGLVQPGGSLRLSCAASGFTFRSYWMTWVRQAPGKGLEW VASINDEGNTKYYVDSLKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARESGLPRGAFQIWGPGTMVTVSS 116 1843 1843 FTFRSYWMT 116 1844 1844 TTCACCTTTAGGAGCTATTGGATGACC 116 1845 1845 SINDEGNTKYYVDSLKG 116 1846 1846 AGCATAAACGATGAGGGGAATACTAAATACTATGTGGACTCTCTGAA GGGC 116 1847 1847 ARESGLPRGAFQI 116 1848 1848 GCGAGGGAGTCCGGTCTGCCCCGGGGTGCCTTTCAAATC 116 1849 1849 GAAATTGTATTGACACAGTCTCCAGTCACCCTGTCTTTGTCTCCAGGG GAAAGAGCCACCCTCTCATGCAGGGCCAGTCAGAGTGTTGGCACCTT CTTAGCCTGGTATCAACACAAACCTGGCCAGGCTCCCAGGCTCCTCAT CTATGATGCATCCAACAGGGCCTCTGCCATCCCAGCCAGGTTCAGTG GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAG CCTGAAGATTTTGCAGTTTATTACTGTCAGCATCGTAGCGACTGGTGG ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 116 1850 1850 EIVLTQSPVTLSLSPGERATLSCRASQSVGTFLAWYQHKPGQAPRLLIYD ASNRASAIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHRSDWWTFGQG TKVEIK 116 1851 1851 RASQSVGTFLA 116 1852 1852 AGGGCCAGTCAGAGTGTTGGCACCTTCTTAGCC 116 1853 1853 DASNRAS 116 1854 1854 GATGCATCCAACAGGGCCTCT 116 1855 1855 QHRSDWWT 116 1856 1856 CAGCATCGTAGCGACTGGTGGACG 117 1857 1857 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGA GACCCTGTCCCTCACCTGCCAAGTCTATGGTGTGTCCTTCAGTGATTA CTACTGGAACTGGATCCGCCAGTCCCCAGGGAAGGGACTGGAGTGGA TTGGGGACGTCAATCATATTGGAAACACCGACTACAACCCGTCCCTC AAGAGTCGAGTCTCCATATCAGTAGACACGTCCAAGAACCAGTTCTC CCTCACCCTGCGCTCTGTGACCGCCGCAGACACGGCTCTATACTACTG TGCGAGAGGCCGTAAACTTTTTGAAGTGCCTCCCAAGGCCCCCGACT ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 117 1858 1858 QVQLQQWGAGLLKPSETLSLTCQVYGVSFSDYYWNWIRQSPGKGLEWI GDVNHIGNTDYNPSLKSRVSISVDTSKNQFSLTLRSVTAADTALYYCARG RKLFEVPPKAPDYWGQGTLVTVSS 117 1859 1859 VSFSDYYWN 117 1860 1860 GTGTCCTTCAGTGATTACTACTGGAAC 117 1861 1861 DVNHIGNTDYNPSLKS 117 1862 1862 GACGTCAATCATATTGGAAACACCGACTACAACCCGTCCCTCAAGAGT 117 1863 1863 ARGRKLFEVPPKAPDY 117 1864 1864 GCGAGAGGCCGTAAACTTTTTGAAGTGCCTCCCAAGGCCCCCGACTAC 117 1865 1865 GATATTGTGATGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTGAGCAGCAC CTACTTAGCCTGGTACCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCC TCATCTATGGTGCGTCCATCAGGGCCACTGGCATCCCAGACAGGTTCA GTGGCGTTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG GAGCCTGAAGATGTTGCAGTGTATTACTGTCAGCAGTATGGGAGCTC ACCTCAGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 117 1866 1866 DIVMTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQAPRLLIY GASIRATGIPDRFSGVGSGTDFTLTISRLEPEDVAVYYCQQYGSSPQTFGQ GTKVEIK 117 1867 1867 RASQSVSSTYLA 117 1868 1868 AGGGCCAGTCAGAGTGTGAGCAGCACCTACTTAGCC 117 1869 1869 GASIRAT 117 1870 1870 GGTGCGTCCATCAGGGCCACT 117 1871 1871 QQYGSSPQT 117 1872 1872 CAGCAGTATGGGAGCTCACCTCAGACG 118 1873 1873 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGATTCAGCCTGGGGC GTCCCTGAGACTCTCCTGTGGAGCCTATGGATTCAGTTTCAGCAGCTC TGCCATGAGCTGGGTCCGCCAGGCTCCAGGTAAGGGGCTGGAGTGGG TCTCAGCTATTAGTGATAATGGTGGTAGCACATACTACGCAGACTCCG TGCAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAACTGAACAGGCTGAGAGCCGAGGACACGGCCATATATTA CTGTGCGAAAGCATATTGTAGTGATAGCTGCCACGGGGGCTACTTTG ACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 118 1874 1874 QVQLVESGGGLIQPGASLRLSCGAYGFSFSSSAMSWVRQAPGKGLEWVS AISDNGGSTYYADSVQGRFTISRDNSKNTLYLQLNRLRAEDTAIYYCAK AYCSDSCHGGYFDYWGQGTLVTVSS 118 1875 1875 FSFSSSAMS 118 1876 1876 TTCAGTTTCAGCAGCTCTGCCATGAGC 118 1877 1877 AISDNGGSTYYADSVQG 118 1878 1878 GCTATTAGTGATAATGGTGGTAGCACATACTACGCAGACTCCGTGCA GGGC 118 1879 1879 AKAYCSDSCHGGYFDY 118 1880 1880 GCGAAAGCATATTGTAGTGATAGCTGCCACGGGGGCTACTTTGACTAC 118 1881 1881 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG GATAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTC CTTCGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT CTATGCTGTATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCACCCTAGAG CCTGAAGACTTTGCAGTTTATTACTGTCAGCAGCGTAGCACCTGGCCG CTCACTTTCGGCCCTGGGACCAAGGTGGAGATCAAA 118 1882 1882 EIVLTQSPATLSLSPGDRATLSCRASQSVSSSFAWYQQKPGQAPRLLIYAV SNRATGIPARFSGSGSGTDFTLTISTLEPEDFAVYYCQQRSTWPLTFGPGT KVEIK 118 1883 1883 RASQSVSSSFA 118 1884 1884 AGGGCCAGTCAGAGTGTTAGCAGCTCCTTCGCC 118 1885 1885 AVSNRAT 118 1886 1886 GCTGTATCCAACAGGGCCACT 118 1887 1887 QQRSTWPLT 118 1888 1888 CAGCAGCGTAGCACCTGGCCGCTCACT 119 1889 1889 GAGGTGCAGCTGTTGGAGTCGGGGGGAGGCTTGGTGAAGCCTGGGGG GTCCCTAAGACTCTCATGTGCAGCCTCTGGATTCATTTTCACTAACGC CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TTGGCCGTATTAAAAGGAAAACTGAAACTGGGACAACAGACTACGCT CCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAGAAG CACGCTGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCG TGTATTACTGTACGACAGGCCCACCCTATCAGTACTATGACAGTACTG GTTATTCGGTCGTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 119 1890 1890 EVQLLESGGGLVKPGGSLRLSCAASGFIFTNAWMSWVRQAPGKGLEWV GRIKRKTETGTTDYAPPVKGRFTISRDDSRSTLYLQMNSLKTEDTAVYYC TTGPPYQYYDSTGYSVVDYWGQGTLVTVSS 119 1891 1891 FIFTNAWMS 119 1892 1892 TTCATTTTCACTAACGCCTGGATGAGC 119 1893 1893 RIKRKTETGTTDYAPPVKG 119 1894 1894 CGTATTAAAAGGAAAACTGAAACTGGGACAACAGACTACGCTCCACC CGTGAAAGGC 119 1895 1895 TTGPPYQYYDSTGYSVVDY 119 1896 1896 ACGACAGGCCCACCCTATCAGTACTATGACAGTACTGGTTATTCGGTC GTTGACTAC 119 1897 1897 TCCTATGAGCTGACTCAGCCACCCTCAGCGTCCGGGACCCCCGGGCA GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTA ACATCGGAATTAATTATGTATACTGGTACCAGCAGCTCCCAGGAACG GCCCCCAAACTCCTCATCTACAGTACTAATCAGCGGCCCTCAGGGGTC CCTGACCGATTCTCTGGCTCCCAGTCTGGCACCTCAGCCTCCCTGGCC ATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC ATGGGATGACAGCCTGAGTGGTCCGGTGTTCGGCGGAGGGACCAAGC TCACCGTCCTA 119 1898 1898 SYELTQPPSASGTPGQRVTISCSGSSSNIGSNIGINYVYWYQQLPGTAPKL LIYSTNQRPSGVPDRFSGSQSGTSASLAISGLRSEDEADYYCAAWDDSLS GPVFGGGTKLTVL 119 1899 1899 SGSSSNIGSNIGINYVY 119 1900 1900 TCTGGAAGCAGCTCCAACATCGGAAGTAACATCGGAATTAATTATGT ATAC 119 1901 1901 STNQRPS 119 1902 1902 AGTACTAATCAGCGGCCCTCA 119 1903 1903 AAWDDSLSGPV 119 1904 1904 GCAGCATGGGATGACAGCCTGAGTGGTCCGGTG 120 1905 1905 CAGGTGCAGCTGGTGCAGTCTGGACCAGAGTTGAAAAAGCCCGGGGA GTCTCTGAAGATCTCCTGTAAGGCTTCTGGATACAGCTTTACCTCCTT CTGGATCGCTTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTTTC TGGGGATCATCTATCCTGGTGACGCTGACACCAGATACAGTCCGTCCT TCCAAGGCCAAGTCACCATCTCAGCCGACAAGTCCATCAACACCGCC TACCTGCAGTGGAACAACCTGAAGGCCTCGGACACCGCCATGTATTA CTGTGCGAGACAGACTACGATGACCCCCGATGCTTTTGATCTCTGGGG CCAAGGGACCACGGTCACCGTCTCCTCA 120 1906 1906 QVQLVQSGPELKKPGESLKISCKASGYSFTSFWIAWVRQMPGKGLEFLGI IYPGDADTRYSPSFQGQVTISADKSINTAYLQWNNLKASDTAMYYCARQ TTMTPDAFDLWGQGTTVTVSS 120 1907 1907 YSFTSFWIA 120 1908 1908 TACAGCTTTACCTCCTTCTGGATCGCT 120 1909 1909 IIYPGDADTRYSPSFQG 120 1910 1910 ATCATCTATCCTGGTGACGCTGACACCAGATACAGTCCGTCCTTCCAA GGC 120 1911 1911 ARQTTMTPDAFDL 120 1912 1912 GCGAGACAGACTACGATGACCCCCGATGCTTTTGATCTC 120 1913 1913 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG GAAAGAGCCACTATCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTA CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATGAAGCATCCGACAGGGCCACTGGCACCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGA GCCTGAGGATTTTGCAGTTTATTACTGTCAGCAGCGTAGTAACTGGGG GGTAGGAACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 120 1914 1914 EIVLTQSPATLSLSPGERATISCRASQSVSSYLAWYQQKPGQAPRLLIYEA SDRATGTPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWGVGTFGQ GTKVEIK 120 1915 1915 RASQSVSSYLA 120 1916 1916 AGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCC 120 1917 1917 EASDRAT 120 1918 1918 GAAGCATCCGACAGGGCCACT 120 1919 1919 QQRSNWGVGT 120 1920 1920 CAGCAGCGTAGTAACTGGGGGGTAGGAACG 121 1921 1921 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC CTCGGTGAGGGTCACCTGCAAGGCTTCTGGAGGCACCGTCAGCGACT ATGCAATCACCTGGGTCCGACAGGCGCCTGGACAAGGGCTTGAGTGG ATGGGAGGGTTCATCCCTATGTTTGGTGTCGCAAAGGACGCAGAGAA GTTCCAGGGCAGAGTCACGCTGACTGGGGACAAATCCACGAACGCAG TTTACATGGAGCTGAGCAGCCTGACATCTGAAGACACGGCCGTCTAT TACTGTGCGAGATCGAAGAGACTACCAGCTGGTTTATCTACGTCTGAC TACTACTACTACTATTTGGACGTCTGGGGCAAAGGGACCACGGTCAC CGTCTCCTCA 121 1922 1922 QVQLVQSGAEVKKPGSSVRVTCKASGGTVSDYAITWVRQAPGQGLEW MGGFIPMFGVAKDAEKFQGRVTLTGDKSTNAVYMELSSLTSEDTAVYY CARSKRLPAGLSTSDYYYYYLDVWGKGTTVTVSS 121 1923 1923 GTVSDYAIT 121 1924 1924 GGCACCGTCAGCGACTATGCAATCACC 121 1925 1925 GFIPMFGVAKDAEKFQG 121 1926 1926 GGGTTCATCCCTATGTTTGGTGTCGCAAAGGACGCAGAGAAGTTCCA GGGC 121 1927 1927 ARSKRLPAGLSTSDYYYYYLDV 121 1928 1928 GCGAGATCGAAGAGACTACCAGCTGGTTTATCTACGTCTGACTACTA CTACTACTATTTGGACGTC 121 1929 1929 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG GAAGGAGCCACCCTCTCCTGTACGGCCAGTCAGAATGTTTTCCGCACC CACGTAGCCTGGTACCAGCAGACTCCTGGCCAGGCTCCCAGGCTCCT CATCTATGGTGGGTCCACCAGGGCCACTGGCATCCCAGACAGGTTCA GTGGCAGCGGGTCTGGGACAGACTTCACTCTCATCATCAGCAGACTG GAACCTGAAGATTTTGCAGTCTATTACTGTCATCACTTTGGTACCACA CCGTGGACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 121 1930 1930 EIVLTQSPGTLSLSPGEGATLSCTASQNVFRTHVAWYQQTPGQAPRLLIY GGSTRATGIPDRFSGSGSGTDFTLIISRLEPEDFAVYYCHHFGTTPWTFGQ GTKVEIK 121 1931 1931 TASQNVFRTHVA 121 1932 1932 ACGGCCAGTCAGAATGTTTTCCGCACCCACGTAGCC 121 1933 1933 GGSTRAT 121 1934 1934 GGTGGGTCCACCAGGGCCACT 121 1935 1935 HHFGTTPWT 121 1936 1936 CATCACTTTGGTACCACACCGTGGACG 122 1937 1937 GAGGTGCAGCTGGTGGAGTCTGGGCCTGAGGTGAAGGGGCCTGGGTC CTCGGTGAAAGTCTCATGCGAGGCTTCTGCAGCCACCTTCAGCAACTA CGCTATCAGCTGGGTCCGACAGGCCCCTGGACAAGGGCTTGAGTGGA TGGGAGGGTTCGTCCCTATGTTAGGGACAAGGAACTACGCACAGAAG TTCAAGGGCAGAGTCACTCTGACCGCGGACGTATCCACACATACATT GTACTTGGAGATTGGTAGTCTGAGATTTGAGGACACGGCCGTGTATTA CTGTGCGACAGTGGCCGGTCTGGGAACCAGCTATGGTCGATACCTTG AGTCTTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 122 1938 1938 EVQLVESGPEVKGPGSSVKVSCEASAATFSNYAISWVRQAPGQGLEWM GGFVPMLGTRNYAQKFKGRVTLTADVSTHTLYLEIGSLRFEDTAVYYCA TVAGLGTSYGRYLESWGQGTLVTVSS 122 1939 1939 ATFSNYAIS 122 1940 1940 GCCACCTTCAGCAACTACGCTATCAGC 122 1941 1941 GFVPMLGTRNYAQKFKG 122 1942 1942 GGGTTCGTCCCTATGTTAGGGACAAGGAACTACGCACAGAAGTTCAA GGGC 122 1943 1943 ATVAGLGTSYGRYLES 122 1944 1944 GCGACAGTGGCCGGTCTGGGAACCAGCTATGGTCGATACCTTGAGTCT 122 1945 1945 GACATCCGGATGACCCAGTCTCCATCTTCTGTGTCTGCGTCTCTTGGA GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGATATTAGCACCGC GTTAGCCTGGTATCAGCAGATACCAGGGAAGGCCCCTAAACTCCTGA TCTATGAAGCATCCAGTTTGCAAAGTGGGGTCCCATCCAGGTTCAGG GGCAGTGGATCTGAGACAGACTTCGCTCTCACTATCAGCAGCCTGCA GCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCAAAGAGTTTCCC GTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 122 1946 1946 DIRMTQSPSSVSASLGDRVTITCRASQDISTALAWYQQIPGKAPKLLIYEA SSLQSGVPSRFRGSGSETDFALTISSLQPEDFATYYCQQAKSFPYTFGQGT KVEIK 122 1947 1947 RASQDISTALA 122 1948 1948 CGGGCGAGTCAGGATATTAGCACCGCGTTAGCC 122 1949 1949 EASSLQS 122 1950 1950 GAAGCATCCAGTTTGCAAAGT 122 1951 1951 QQAKSFPYT 122 1952 1952 CAACAGGCAAAGAGTTTCCCGTACACT 123 1953 1953 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGCGCAGCCTGGAGG GTCCCTGAGACTCTCCTGTGCAGCCTCCGGATTCATCTTCAGTGTTTA TGAAATGGACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGC TTTCATACATTGATATTACTGGTAATAGTGTAACCTATGCAGACTCTG TGAGGGGCCGGTTCACCATCTCCAGAGACAACGCCAGGAACTCACTC TACCTGCAAATGGACAGCCTGAGAGTCGAGGACACGGCTGTATATTA TTGTGTTAGAGATAGTCGCGGCCCTACAACGCAGTGGCTCACGGGAT ACTTTGACTTCTGGGGCCAGGGGACCACGGTCACCGTCTCCTCA 123 1954 1954 QVQLVQSGGGLAQPGGSLRLSCAASGFIFSVYEMDWVRQAPGKGLEWL SYIDITGNSVTYADSVRGRFTISRDNARNSLYLQMDSLRVEDTAVYYCV RDSRGPTTQWLTGYFDFWGQGTTVTVSS 123 1955 1955 FIFSVYEMD 123 1956 1956 TTCATCTTCAGTGTTTATGAAATGGAC 123 1957 1957 YIDITGNSVTYADSVRG 123 1958 1958 TACATTGATATTACTGGTAATAGTGTAACCTATGCAGACTCTGTGAGG GGC 123 1959 1959 VRDSRGPTTQWLTGYFDF 123 1960 1960 GTTAGAGATAGTCGCGGCCCTACAACGCAGTGGCTCACGGGATACTT TGACTTC 123 1961 1961 GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAACTA CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATGATGTATCCAATAGGGCCACTGGCATCCCAGCCAGGTTCAGTG GCAGTGGGTCCGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAG CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTCGCAACTGGCCT CCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGGTCAAA 123 1962 1962 DIRMTQSPATLSLSPGERATLSCRASQSVSNYLAWYQQKPGQAPRLLIYD VSNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPPLTFGG GTKVEVK 123 1963 1963 RASQSVSNYLA 123 1964 1964 AGGGCCAGTCAGAGTGTTAGCAACTACTTAGCC 123 1965 1965 DVSNRAT 123 1966 1966 GATGTATCCAATAGGGCCACT 123 1967 1967 QQRRNWPPLT 123 1968 1968 CAGCAGCGTCGCAACTGGCCTCCGCTCACT

ADDITIONAL EMBODIMENTS Embodiment 1

An isolated antibody or an antigen-binding fragment thereof that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics:

a) the antibody or antigen-binding fragment thereof cross-competes with said antibody or antigen-binding fragment thereof for binding to RSV-F;

b) the antibody or antigen-binding fragment thereof displays better binding affinity for the PreF form of RSV-F relative to the PostF form;

c) the antibody or antigen-binding fragment thereof displays a clean or low polyreactivity profile;

d) the antibody or antigen-binding fragment thereof displays neutralization activity toward RSV subtype A and RSV subtype B in vitro;

e) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F at Site ø, Site I, Site II, Site III, Site IV, or Site V;

f) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F Site ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV;

g) at least a portion of the epitope with which the antibody or antigen-binding fragment thereof interacts comprises the α3 helix and β3/β4 hairpin of PreF;

h) the antibody or antigen-binding fragment thereof displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml;

i) the binding affinity and/or epitopic specificity of the antibody or antigen-binding fragment thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1;

j) the antibody or antigen-binding fragment thereof of displays a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV);

k) the antibody or antigen-binding fragment thereof does not complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or

l) the antibody or antigen-binding fragment thereof displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.

Embodiment 2

The isolated antibody or antigen-binding fragment thereof of Embodiment 1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1).

Embodiment 3

The isolated antibody or antigen-binding fragment thereof of Embodiment 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises:

a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; or

g) any combination of two or more of a), b), c), d), e), and f).

Embodiment 4

The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 3, wherein the antibody or antigen-binding fragment thereof comprises:

a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and/or

b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

Embodiment 5

The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

Embodiment 6

The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody 1 through Antibody Number 123 as disclosed in Table 6.

Embodiment 7

An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of Embodiments 1 through 6.

Embodiment 8

An expression vector comprising the isolated nucleic acid sequence according to Embodiment 7.

Embodiment 9

A host cell transfected, transformed, or transduced with the nucleic acid sequence according to Embodiment 7 or the expression vector according to Embodiment 8.

Embodiment 10

A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of Embodiments 1 through 6; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 11

A pharmaceutical composition comprising: one or more nucleic acid sequences according to Embodiment 7; or one or more the expression vectors according to Embodiment 8; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 12

A transgenic organism comprising the nucleic acid sequence according to Embodiment 7; or the expression vector according to Embodiment 8.

Embodiment 13

A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments 1 through 6;

b) a nucleic acid sequences according to Embodiment 7;

c) an expression vector according to Embodiment 8;

d) a host cell according to Embodiment 9; or

e) a pharmaceutical composition according Embodiment 10 or Embodiment 11;

such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

Embodiment 14

A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments 1 through 6;

b) a nucleic acid sequences according to Embodiment 7;

c) an expression vector according to Embodiment 8;

d) a host cell according to Embodiment 9; or

e) a pharmaceutical composition according Embodiment 10 or Embodiment 11;

such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

Embodiment 15

The method according to Embodiment 14, wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 4, 11, or 62 as disclosed in Table 6.

Embodiment 16

The method according to any one of Embodiments 13 through 15, wherein the method further comprises administering to the patient a second therapeutic agent.

Embodiment 17

The method according to Embodiment 16, wherein the second therapeutic agent is selected from the group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

Embodiment 18

A pharmaceutical composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof of any one of Embodiments 1 through 7 and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 19

The pharmaceutical composition according to Embodiment 18 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment 20

The pharmaceutical composition according to Embodiment 18 for use in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment 21

Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

Embodiment 22

Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment A1

An isolated antibody or an antigen-binding fragment thereof that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one, at least two of, at least three of, at least four of, at least five of, or six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; at least 100% and/or all percentages of identity in between; to at least one of, at least two of, at least three of, at least four of, at least five of, or six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics:

a) the antibody or antigen-binding fragment thereof cross-competes with said antibody or antigen-binding fragment thereof for binding to RSV-F;

b) the antibody or antigen-binding fragment thereof displays better binding affinity for the PreF form of RSV-F relative to the PostF form;

c) the antibody or antigen-binding fragment thereof displays a clean or low polyreactivity profile;

d) the antibody or antigen-binding fragment thereof displays neutralization activity toward RSV subtype A and RSV subtype B in vitro;

e) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F at Site ø, Site I, Site II, Site III, Site IV, or Site V;

f) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F Site ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV;

g) at least a portion of the epitope with which the antibody or antigen-binding fragment thereof interacts comprises the α3 helix and β3/β4 hairpin of PreF;

h) the antibody or antigen-binding fragment thereof displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 μg/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml;

i) the binding affinity and/or epitopic specificity of the antibody or antigen-binding fragment thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1;

j) the antibody or antigen-binding fragment thereof of displays a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV);

k) the antibody or antigen-binding fragment thereof does not complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or

l) the antibody or antigen-binding fragment thereof displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC₅₀) than D25 and/or palivizumab.

Embodiment A2

The isolated antibody or antigen-binding fragment thereof of Embodiment A1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1).

Embodiment A3

The isolated antibody or antigen-binding fragment thereof of Embodiment A1 or A2, wherein the antibody or antigen-binding fragment thereof comprises:

a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6;

f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; or

g) any combination of two or more of a), b), c), d), e), and f).

Embodiment A4

The isolated antibody or antigen-binding fragment thereof of any one of Embodiments A1 through A3, wherein the antibody or antigen-binding fragment thereof comprises:

a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and/or

b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

Embodiment A5

The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table 6.

Embodiment A6

The isolated antibody or antigen-binding fragment thereof of any one of Embodiments A1 through A5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody 1 through Antibody Number 123 as disclosed in Table 6.

Embodiment A7

An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of Embodiments A1 through A6.

Embodiment A8

An expression vector comprising the isolated nucleic acid sequence according to Embodiment A7.

Embodiment A9

A host cell transfected, transformed, or transduced with the nucleic acid sequence according to Embodiment A7 or the expression vector according to Embodiment A8.

Embodiment A10

A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of Embodiments A1 through A6; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment A11

A pharmaceutical composition comprising: one or more nucleic acid sequences according to Embodiment A7; or one or more the expression vectors according to Embodiment A8; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment A12

A pharmaceutical composition comprising a first nucleic acid sequence encoding the light chain of an antibody or antigen-binding fragment according to any one of Embodiments A1 through A6 and a second nucleic acid sequence encoding the heavy chain of an antibody or antigen binding fragment according to any one of Embodiments A1 through A6.

Embodiment A13

A first pharmaceutical composition comprising a first nucleic acid sequence encoding the light chain of an antibody or antigen-binding fragment according to any one of Embodiments A1 through A6 and a second pharmaceutical composition comprising a second nucleic acid sequence encoding the heavy chain of an antibody or antigen binding fragment according to any one of Embodiments A1 through A6, wherein upon coadministration of the first and second pharmaceutical compositions to the subject, an antibody of the invention or antigen binding fragment thereof is expressed in the subject.

Embodiment A14

A transgenic organism comprising the nucleic acid sequence according to Embodiment A7 or the expression vector according to Embodiment A8.

Embodiment A15

A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments A1 through A6;

b) a nucleic acid sequences according to Embodiment A7;

c) an expression vector according to Embodiment A8;

d) a host cell according to Embodiment A9; or

e) a pharmaceutical composition according to any one of Embodiment A10 through Embodiment A13, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

Embodiment A16

A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments A1 through A6;

b) a nucleic acid sequences according to Embodiment A7;

c) an expression vector according to Embodiment A8;

d) a host cell according to Embodiment A9; or

e) a pharmaceutical composition according to any one of Embodiment A10 through Embodiment A13, such that the RSV infection and/or HMPV infection is treated or prevented, or the at least on symptom associated with RSV infection and/or HMPV infection is treated, alleviated, or reduced in severity.

Embodiment A17

The method according to Embodiment A16, wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 4, 11, or 62 as disclosed in Table 6.

Embodiment A18

The method according to any one of Embodiments A15 through A17, wherein the method further comprises administering to the patient a second therapeutic agent.

Embodiment A19

The method according to Embodiment A18, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

Embodiment A20

A pharmaceutical composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof or a nucleic acid molecule encoding said isolated antibody or antigen-binding fragment thereof of any one of Embodiments A1 through A7 and a pharmaceutically acceptable carrier and/or excipient.

Embodiment A21

The pharmaceutical composition according to Embodiment A20 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment A22

The pharmaceutical composition according to Embodiment A20 for use in treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection(s) is/are either prevented, or at least one symptom or complication associated with the infection(s) is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment A23

Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

Embodiment A24

Use of the pharmaceutical composition of Embodiment A20 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection(s) is/are either prevented, or at least one symptom or complication associated with the infection(s) is prevented, ameliorated, or lessened in severity and/or duration as a result of such use. 

What is claimed is:
 1. An isolated antibody or an antigen-binding fragment thereof that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F) (“anti-RSV F antibody”), wherein at least one of a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the anti-RSV F antibody is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one of a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequence of an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and wherein the anti-RSV F antibody has one or more of the following characteristics: a) the anti-RSV F antibody cross-competes with an antibody selected from Antibody Number 1 through Antibody Number 123 as disclosed in Table 6 for binding to RSV-F; b) the anti-RSV F antibody displays better binding affinity for the PreF form of RSV-F relative to the PostF form of RSV-F; c) the anti-RSV F antibody displays a clean or low polyreactivity profile; d) the anti-RSV F antibody displays neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the anti-RSV F antibody displays antigenic site specificity for RSV-F at Site ø, Site I, Site II, Site III, Site IV, or Site V; f) the anti-RSV F antibody displays antigenic site specificity for RSV-F Site ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the anti-RSV F antibody interacts comprises the α3 helix and β3/β4 hairpin of PreF; h) the anti-RSV F antibody displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 ug/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml; i) the binding affinity and/or epitopic specificity of the anti-RSV F antibody for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of anti-RSV F antibody for RSV-F or RSV-F DS-Cav1; j) the anti-RSV F antibody displays a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV); k) the anti-RSV F antibody does not complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or l) the anti-RSV F antibody displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC₅₀) than D25 and/or palivizumab.
 2. The isolated anti-RSV F antibody of claim 1, which comprises: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).
 3. The isolated anti-RSV F antibody of claim 1 or 2, which comprises: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 1 through Antibody Number 123 as disclosed in Table
 6. 4. The isolated anti-RSV F antibody of any one of claims 1 to 3, which is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 1 through Antibody Number 123 as disclosed in Table
 6. 5. An isolated nucleic acid sequence encoding an anti-RSV F antibody according to any one of claims 1 to
 5. 6. An expression vector comprising the isolated nucleic acid sequence according to claim
 5. 7. A host cell transfected, transformed, or transduced with the nucleic acid sequence according to claim 5 or the expression vector according to claim
 6. 8. A pharmaceutical composition comprising one or more of the anti-RSV F antibodies according to any one of claims 1 to 6; one or more nucleic acid sequences according to claim 5; or one or more expression vectors according to claim 6; and a pharmaceutically acceptable carrier and/or excipient.
 9. The pharmaceutical composition according to claim 8 for use in (i) preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use; or (ii) treating or preventing either a RSV infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with the RSV infection or the HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
 10. A pharmaceutical composition comprising a first nucleic acid sequence encoding the light chain of an anti-RSV F antibody according to any one of claims 1 to 4 and a second nucleic acid sequence encoding the heavy chain of an anti-RSV F antibody according to any one of claims 1 to
 4. 11. A first pharmaceutical composition comprising a first nucleic acid sequence encoding the light chain of an anti-RSV F antibody according to any one of claims 1 to 4 and a second pharmaceutical composition comprising a second nucleic acid sequence encoding the heavy chain of an anti-RSV F antibody according to any one of claims 1 to 4, wherein upon coadministration of the first and second pharmaceutical compositions to a subject, the anti-RSV F antibody is expressed in the subject.
 12. A transgenic organism comprising the nucleic acid sequence according to claim 5 or the expression vector according to claim
 6. 13. A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with RSV infection or HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more anti-RSV F antibodies according to any of claims 1 to 4; b) a nucleic acid sequences according to claim 5; c) an expression vector according to claim 6; d) a host cell according to claim 7; or e) a pharmaceutical composition according to any one of claims 8 to 10; such that the RSV infection or HMPV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
 14. The method according to claim 13, wherein the one or more anti-RSV F antibodies is selected from the group consisting of the antibodies designated as Antibody Number 4, 11, or 62 as disclosed in Table
 6. 15. The method according to claim 13 or 14, which further comprises administering to the patient a second therapeutic agent optionally selected from the group consisting of an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody, and a NSAID. 